MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS, Mar. 2006, p. 253–282 Vol. 70, No.

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1092-2172/06/$08.00⫹0 doi:10.1128/MMBR.70.1.253–282.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Glucose Signaling in Saccharomyces cerevisiae

George M. Santangelo*
Department of Biological Sciences, University of Southern Mississippi, Hattiesburg, Mississippi 39406-5018

INTRODUCTION .......................................................................................................................................................253
NATURE OF THE SIGNAL......................................................................................................................................254
Signaling without Extracellular Sensing, Transport, or Phosphorylation of Glucose..................................254
Redundant but Unified Glucose Signaling Pathways ........................................................................................255
Early Steps in Signal Transduction .....................................................................................................................256
The Ras/cAMP/PKA pathway............................................................................................................................256
The Gpr1/Gpa2 pathway ....................................................................................................................................258

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Activation of Ras and Gpa2 by glucose ...........................................................................................................258
(i) Extracellular sensing ................................................................................................................................258
(ii) Intracellular sensing................................................................................................................................258
Extracellular sensing by Snf3/Rgt2 ..................................................................................................................259
SIGNAL RECEPTION: GLUCOSE REPRESSION ..............................................................................................259
Involvement of the Hexokinase Hxk2 in the Glucose Response ......................................................................259
Snf1-Mediated Signal Transduction in Glucose Repression and Derepression ............................................260
Dueling Snf1 kinase and Glc7 phosphatase mediate glucose regulation....................................................260
Transmission of the Ras/cAMP-dependent glucose signal to Reg1/Glc7 and Snf1/Snf4..........................263
DNA-bound repressors controlled by Snf1......................................................................................................263
DNA-bound activators controlled by Snf1.......................................................................................................265
SIGNAL RECEPTION: GLUCOSE INDUCTION.................................................................................................265
Snf3/Rgt2 Signaling of the Rgt1 Repressor Complex ........................................................................................265
The Cell Cycle Connection ....................................................................................................................................267
Transcriptional Induction of Glycolytic and Ribosomal Protein Genes .........................................................268
The Repressor/Activator Theme in Glucose Regulation....................................................................................269
Reverse Recruitment: Rap1/Gcr1 Activation at the Nuclear Periphery..........................................................269
GENE REGULATION VIA REVERSE RECRUITMENT.....................................................................................272
A New Model for Eukaryotic Transcriptional Activation and Repression .....................................................272
Glucose May Signal a Highly Networked and Structurally Stable Perinuclear Machine............................273
ACKNOWLEDGMENTS ...........................................................................................................................................274
REFERENCES ............................................................................................................................................................274

INTRODUCTION repression and glucose induction). The response to glucose

Jacques Monod’s seminal discovery of the diauxic growth of
bacterial cultures (243) demonstrated that microbes are par-
ticularly adept at targeting and responding to glucose, the most
abundant monosaccharide in nature. A wealth of subsequent
work has shown that virtually all cells possess a sophisticated
genetic program that responds to this rich source of carbon
and energy. Study of the glucose response in eukaryotes has
been greatly aided by the development of the malleable bud-
ding yeast Saccharomyces cerevisiae as a model system (see,
e.g., references 361 and 417). S. cerevisiae shares with complex
multicellular eukaryotes many of the signal transduction com-
ponents that detect glucose, transduce the corresponding sig-
nals to the interior of the cell, and make the needed adjust-
ments to cellular metabolism and gene expression profiles.
This review will focus on the cytoplasmic regulators that
transmit the glucose signal from the plasma membrane into the
yeast nucleus, as well as the nuclear apparatus that mediates
the global transcriptomic response to the sugar (both glucose
* Mailing address: Department of Biological Sciences, University of
Southern Mississippi, Hattiesburg, MS 39406-5018. Phone: (601) 266-
6080. Fax: (601) 266-5068. E-mail: George.Santangelo@mfgn.usm.edu.
also involves direct modification of metabolic pathways (termed
glucose or catabolite inactivation) and other processes such as
mRNA turnover (7, 76, 103, 121, 153, 154, 156, 161, 166,
171–173, 232, 294, 307, 329, 334, 335, 337, 391). Although the
latter phenomena are outside the scope of this review, they
appear to be mediated by the same two central signal trans-
duction pathways, Ras/cyclic AMP (cAMP)/protein kinase A
(PKA) and Snf3/Rgt2/Yck, which are described below in
detail.
The recent application of yeast genomics and proteomics is
a first step towards comprehensive characterization of the glu-
cose response. For example, we now know that within 20 min
of glucose addition, ⬃20% of the roughly 6,200 genes in S.
cerevisiae exhibit a greater-than-threefold change in expression
(either induction or repression), and ⬃40% show at least a
twofold change (408). Glucose repression largely affects genes
encoding enzymes involved in respiration or alternative carbon
source metabolism, and glucose induction stimulates transcrip-
tion of glycolytic genes and ribosomal protein (RP) genes (see
below). Genomic and proteomic analyses are particularly use-
ful when supplemented with high-throughput genetic tech-
niques such as synthetic genetic array analysis, which allows the
identification of synthetic phenotypes by simultaneous screen-

253
254 SANTANGELO MICROBIOL. MOL. BIOL. REV.

ing of the entire collection of mutants in which each of the

⬃4,700 nonessential yeast genes has been deleted (373).
The continued pursuit of such large data sets, in combina-
tion with the now-facile elimination, overexpression, or point
mutation of relevant yeast regulators, should eventually permit
the delineation of a global wiring diagram that mirrors its
biological template when virtually challenged with a wide
range of concentrations of the sugar. For such a computational
model to be valid, it must at a minimum be informed by (i) an
accurate molecular map of cytoplasmic and nuclear substruc-
ture, (ii) a detailed diagram of the physical and functional
connections that link the relevant signal transduction compo-
nents to each other and to adjacent networks, and (iii) the
temporal progression of the response following the appearance

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of glucose. Here I review our progress toward that ambitious
goal and attempt to identify the most important issues that
require further clarification.

NATURE OF THE SIGNAL

Two recent surprises uncovered by global analyses of Saccha-
romyces cerevisiae are the extent to which the glucose induction
and repression mechanisms appear to overlap and the fact that
yeast cells can be tricked into generating the full-blown response
(both induction and repression) in the complete absence of glu-
cose. These and other recent developments place G-protein sig-
naling, in particular the Ras/cAMP/PKA pathway, front and cen-
ter among the cellular components that participate in early events
in the glucose response.

Signaling without Extracellular Sensing, Transport,

or Phosphorylation of Glucose
A recent microarray experiment from the Broach laboratory
has clearly demonstrated the universality of induction/repres-
sion overlap in glucose signal transduction. A unified transcrip-
tome-wide response (both upshifted and downshifted gene ex-
pression) was observed in yeast cells by stimulating early steps
in the glucose signaling pathway; a clever experimental scheme
allowed the generation and detection of this comprehensive
glucose response without addition of the sugar (408). The yeast
transcriptome was analyzed after heterologous induction of
activated alleles of Ras2 or Gpa2, signal transmitters that act in
parallel early in the cAMP-dependent protein kinase (PKA)
pathway (see below). Astonishingly, virtually all of the changes
in transcript levels after addition of glucose (both up-regula-
tion and down-regulation) were also observed in the absence of
glucose following expression of the activated form of Ras2. Of
the genes that showed at least a threefold change in expression
within an hour following glucose addition, almost all (92%)
changed at least twofold in the same direction after Ras acti-
vation (Fig. 1; Table 1). The result was similar with activated
Gpa2, though the intensity of the transcriptional response was
reduced relative to that seen with activated Ras. Those authors
also demonstrated that all of the changes in transcript levels
resulting from Ras2 and Gpa2 activation were mediated by
PKA (408) (Fig. 1). Importantly, since much of this transcrip-
tional reprogramming can also be accomplished in the absence
of signaling through cAMP, redundant overlapping pathways
(Ras2/Gpa2/PKA dependent and Ras2/Gpa2/PKA indepen-
FIG. 1. Wild-type versus Ras2 mimicry of the glucose response.
Each curve represents the expression profile of genes exhibiting a
twofold or greater change, both within 20 min of glucose addition and
within 20 min of the appearance of activated Ras2. The average values
for 250 such induced genes (upper graph) and repressed genes (lower
graph) are shown (see supplemental data associated with reference
208); error bars represent standard errors of the means. Squares,
expression profile of wild-type cells following glucose addition; filled
triangles, expression profile of cells containing Gal-regulated Ras2*
(activated Ras) following addition of galactose; open triangles, expres-
sion profile of cells containing Gal-regulated Ras2* (activated Ras) in
a tpkw (weak PKA) background following addition of galactose. It is
important to note that the ⬎100-fold induction and repression ob-
served for a small subset of glucose regulated genes (e.g., HXT genes;
see reference 272) is not seen within the 60-minute time frame of this
data set.
dent) appear to be fully capable of transducing the glucose
signal. Little is known about the PKA-independent mecha-
nism, although it presumably targets a similar set of down-
stream factors in the absence of normal PKA catalytic activity.
The observed transcriptome-wide up-regulation and down-
regulation of gene expression in response to activated Ras was
particularly surprising, since it had long been assumed (despite
early hints to the contrary [see, e.g., reference 233]) that the
primary glucose repression pathways in yeast are distinct from
VOL. 70, 2006 GLUCOSE SIGNALING IN S. CEREVISIAE 255

TABLE 1. Genes that respond similarly to both glucose addition and Ras2 activation a
Induced genes Repressed genes

Protein Energy reserve Protein Stress

Transcription Transportc
biosynthesisb metabolismd turnover response

RPS9A RPA43 NUP1 BCY1 PEP4 HSP30

RPS22B RPA49 NUP100 SDC25 RPN2 SSE2
RPS27A RPB5 NUP133 GAL83 RPN3 SSA3
RPL7B RPB9 NUP170 PHO85 RPN5 SSA4
RPL14B RPC40 MEX67 TPS1 RPN6 SSD1
RPL17B RPC82 RNA1 CIT3 RPN7 STO1
TIF11 RPO26 GSP1 GPD1 RPT1 CDC55
TIF3 RPO31 PSE1 MDH3 RPT3 UBC5
TIF34 RRP43 SXM1 PGM2 RPT4 PRE1
TEF4 RRP45 ALR21 HXT10 RPT5 PRE3
CDC60 RRP5 FET3 MRPL23 DOA1 GTS1
ARG8 ARG80 FET4 MRPL32 DOA4 CRS5

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ARO7 BAS1 FKS1 PET112 APG13 CTA1
ARO8 DBP2 HNM1 PET117 APG14 GRX2
ASP1 DBP3 HXT2 PET191 APC9 TRX2
HIS1 GCR2 HXT4 PET54 HRD1 MDR1
HIS3 IFH1 LYP1 COQ1 HRD3 PAU1
ILS1 HMALPHA1 NPL3 COQ3 PEX14 PAU2
ILV1 IMP4 PHO84 COX10 MPD2 PAU3
LYS4 LEU3 ZRT1 COX11 SBA1 PPZ2
a
See supplemental data associated with reference 408; a grand total of 758 genes exhibited a twofold or greater change in expression both within 20 min of glucose
addition and within 20 min of the appearance of activated Ras2. Gene categories are based on Munich Information Center for Protein Sequences functional
classification; a representative list from each category is shown. A total of 329 and 429 genes were in the induced and repressed categories, respectively.
b
Includes genes encoding translational components (including ribosomal proteins), rRNA-processing factors, and amino acid biosynthetic enzymes.
c
Includes genes encoding nucleocytoplasmic transport factors and plasma membrane transporters.
d
Includes genes encoding factors involved in carbon storage and respiration (including mitochondrial factors).

glucose induction and are also essentially Ras independent (44,
45, 118, 121, 123, 178, 315, 335, 365). Further, stimulation of
the glucose response in the absence of either transport or
phosphorylation of the sugar (408) is particularly significant.
Transport of glucose and its conversion to glucose-6-phosphate
by hexokinases had been explored as a potentially essential
feature of the response (121, 314, 316) and now appears to at
most participate in redundant signaling that operates through
or in parallel with the cAMP-PKA pathway. Whatever extra-
cellular or intracellular glucose sensing is needed to activate
Ras or Gpa2 is therefore sufficient for both glucose induction
and repression. This interpretation has the added advantage of
bringing our assessment of glucose-stimulated signal transduc-
tion in yeast cells closer to what is known about the analogous
response in bacterial and mammalian cells (for reviews, see
references 35, 129, and 322).
Redundant but Unified Glucose Signaling Pathways
The first hint of overlap between glucose induction and
repression resulted from analysis of regulators that are “down-
stream” in the signaling cascade, i.e., factors that for the most
part function within the yeast nucleus. For example, the Rgt1
repressor blocks transcription of HXT1 through HXT4 (4 of
the 18 glucose transporter genes in S. cerevisiae) (see refer-
ences 118 and 272 for reviews). At high glucose concentrations,
although its contact with the HXT1 promoter can no longer be
detected, Rgt1 is converted into an activator through hyper-
phosphorylation (142, 186, 250). The hexokinase Hxk2, long
known to participate in glucose repression, is also required for
glucose induction of HXT1 (231, 271).
The Snf1 serine-threonine kinase represents another exam-
ple of downstream regulatory overlap; Snf1 activates genes
that are repressed in glucose-containing media but are dere-
pressed and needed for growth in the presence of nonferment-
able carbon sources (46). Recent transcriptomic and proteomic
analyses of snf1 cells revealed a previously unnoticed upshift in
expression of genes (e.g., ADH1) involved in glucose catabo-
lism (hereafter the term “glycolytic genes” will be used for this
group) (432). Thus, in addition to its well-established role in
derepressing glucose-repressed genes, Snf1 also somehow re-
presses transcription of glucose-induced genes (including HXT1)
(372). Snf1 repression of glycolytic gene expression has been
further substantiated by proteomic analysis of cells lacking Snf4,
the ␥ subunit of the Snf1 kinase complex (140).
A final example of downstream regulatory overlap is the
phosphoprotein Gcr1, which was first identified as an activator
of glycolytic genes (13, 63, 64, 152). Transcriptomics and other
analyses have confirmed that expression of numerous glucose-
repressed genes is derepressed in the absence of Gcr1 at high
glucose concentrations, suggesting a new role for this regulator
in repression of transcription (327, 383; K. Barbara and G. M.
Santangelo, unpublished data).
The roles of Rgt1, Hxk2, Snf1/Snf4, and Gcr1, as well as
numerous other repressor/activator polypeptides that partici-
pate in the glucose response, are presented in greater detail in
later sections of this review. In addition to these specific reg-
ulators, at least eight components of the general transcription
machinery that interact with the carboxy-terminal domain of
RNA polymerase II (Gal11, Sin4, Rgr1, Rox3, Srb8, Ssn2,
Ssn3, and Ssn8) have been found to play both positive and
negative regulatory roles; the function of many of these factors
256 SANTANGELO
is known to be influenced by glucose signaling (43, 195). Thus,
the overlapping positive and negative circuitry in the glucose
response may extend from the plasma membrane through to
the ultimate choice of induction or shutoff of transcription initi-
ation of each glucose-regulated gene by RNA polymerase II.
The induction/repression duality of signal recipients such as
Rgt1, Hxk2, Snf1/Snf4, Gcr1, and other transcription factors
clearly requires further characterization of the precise mecha-
nisms involved. Nonetheless, together with the transcriptomic
analysis of activated Ras, it suggests the existence of a more
unified and interdigitated response to glucose than had previ-
ously been appreciated. Although it now seems certain that
transmission of the glucose signal is redundant (408), those
signaling pathways may converge on only a relatively small
group of transcription factors in the yeast nucleus (see below).
Coordinated remodeling of the nuclear regulatory apparatus in
response to glucose might therefore involve a parsimonious
series of alterations in key regulators. Although for the sake of
clarity and historical perspective the discussion of nuclear reg-
ulators is divided into separate sections of this review, in reality
the mechanisms of “glucose repression” and “glucose induc-
tion” may be no more segregated than the two faces of a coin.
Early Steps in Signal Transduction
Given the sufficiency of Ras or Gpa2 activation to produce
the transcriptome-wide spectrum of changes in response to
glucose, it is important first to review what is known about
these factors, their respective signaling pathways, and how they
are activated immediately following appearance of the sugar.
The Ras/cAMP/PKA pathway. Ras proteins are monomeric
GTPases that function as switches; these so-called G proteins
are inactive in the GDP-bound state and active when GTP is
bound. The switch from the active to the inactive form involves
hydrolysis of bound GTP by the intrinsic GTPase and is stim-
ulated by GTPase-activating proteins (GAPs). The reverse (in-
active-to-active) switch requires replacement of bound GDP
with GTP, which is normally accomplished with the aid of
guanine nucleotide exchange factors (GEFs). Activating mu-
tations in Ras polypeptides (e.g., human rasVal12 or yeast
Ras2Val19) increase GTP association in a GEF-independent
fashion and are responsible for many human cancers (78, 419).
Ras mutations are found in approximately 30% of human
tumors; the frequency of oncogenic forms of Ras is as high as
50% or 90% in colorectal or pancreatic tumors, respectively
(345). Although it remains dimly understood, it seems likely
that there is an important connection between these recent
data and a very old observation that altered glucose metabo-
lism is a hallmark of cancerous cells in solid tumors (71, 179).
The polypeptides encoded by the two RAS genes in S.
cerevisiae, Ras1 (309 residues) and Ras2 (322 residues), are
⬎70% identical overall and approximately 90% identical over
the N-terminal 180 residues (291). Growth on glucose is unaf-
fected by the absence of either Ras1 or Ras2, whereas loss of
both causes arrest in the G1 phase of the cell cycle (362, 367).
These early findings were suggestive of a connection to nutri-
ent sensing, since nutrient-deprived cells also arrest in G1
phase. Overexpression of RAS1 was also found to suppress the
MICROBIOL. MOL. BIOL. REV.
failure of ras2⌬ cells to grow on nonfermentable carbon
sources (363), suggesting that the latter defect is due to the fact
that Ras1 is more weakly expressed than Ras2 (249, 361),
rather than a specific function that maps to the divergent and
slightly extended C terminus of Ras2.
Important effector molecules modulate Ras activity during
the glucose response; posttranslational modification and mem-
brane localization of Ras are two important features of these
regulatory inputs. For example, Ras farnesylation contributes
to nucleotide exchange by the GEF Cdc25 (34, 73, 134);
CDC25 is an essential gene and was originally identified by a
screen for mutations that cause G1 arrest (139). A second yeast
RasGEF that can substitute for Cdc25 when overexpressed is
encoded by the dispensable SDC25 gene (31) (note that this
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gene was originally named SCD25 [79]).
Ras stimulation by the RasGEFs in turn stimulates produc-
tion of cAMP by the essential product of the adenylate cyclase
gene (CYR1) (229). Inactivation of Ras, resulting in lower
cAMP levels, is facilitated by the GAPs Ira1 and Ira2 (358,
360) (Fig. 2). Presumably due to their competing effects on Ras
activation, IRA1 deletion rescues the lethality caused by dele-
tion of the RasGEF CDC25 (359). Low-affinity and high-affin-
ity cAMP phosphodiesterases in S. cerevisiae (Pde1 and Pde2,
respectively) also antagonize the Ras signal through enzymatic
removal of cAMP; in the presence of exogenous cAMP, dele-
tion of PDE2 restores growth to ras1⌬ ras2⌬ strains (266, 420).
The Ras C terminus also undergoes functionally significant
posttranslational modification. Yeast Ras2 is normally pal-
mitoylated via a thioester linkage at cysteine 318 and farnesy-
lated via a thioether linkage at cysteine 319. Blocking both
modifications with the double point mutation C318S C319S
results in a nonfunctional molecule (92). Farnesylation is re-
quired for palmitoylation and all subsequent modifications,
which include removal of the three C-terminal residues by
proteolytic cleavage and methyl esterification of the revealed
C-terminal cysteine 319 (19).
The palmitoyl moiety anchors Ras to the cytoplasmic face of
the yeast plasma membrane (199); blocking addition of palmi-
tate via the single point mutation C318S causes mislocalization
of the mutated Ras2 protein to the cytoplasm (176). Ras pal-
mitoylation is reversible and therefore may be a regulatory
step. This is of particular interest because mutation of pal-
mitoylation sites abrogates both the glucose response in yeast
cells (see below) and transformation of mammalian cells by
oncogenic forms of Ras (418).
The appearance of glucose thus generates one or more sig-
nals that converge on membrane-bound Ras and its modifiers
(in particular the RasGEFs and RasGAPs). This glucose sig-
naling results in a rapid but transient spike in the level of
intracellular cAMP, which increases 5- to 50-fold within 1 to 2
min of glucose addition and returns to near-basal levels within
20 min. When cells express the nonpalmitoylated cytoplasmic
Ras2C318S form as their only Ras protein, they fail to exhibit
the glucose-induced cAMP spike and are defective in transi-
tioning to rapid growth upon addition of glucose (160). Thus,
glucose-regulated cAMP production appears to require attach-
ment of Ras to the yeast plasma membrane. Interestingly,
membrane localization of yeast Ras2 was recently shown to
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FIG. 2. Cytoplasmic events in PKA signaling. Glucose regulation relies upon the intracellular signaling molecule (“second messenger”) cAMP.
GTP-bound G proteins (Ras and Gpa2) bind independently to adenylate cyclase (Cyr1) and stimulate its production of cAMP. The monomeric
Ras G proteins are anchored in the plasma membrane via a posttranslationally added palmitoyl moiety (red squiggle). RasGEFs (Cdc25 and Sdc25)
and RasGAPs (Ira1 and Ira2) are also present in the Ras/Cyr1 complex and regulate adenylate cyclase by controlling the Ras switch (see text).
The seven-transmembrane polypeptide Gpr1 acts upstream of Gpa2 in glucose signaling and is a member of the G protein-coupled receptor
(GPCR) superfamily. Gpa2 was identified as a result of its similarity to the mammalian G␣ subunits of heterotrimeric G proteins, and the putative
G␤ subunits Gpb1 and Gpb2 were found via their interaction with Gpa2; a corresponding ␥ subunit has yet to be identified (question mark). A
Gpa2GEF also awaits identification; Rgs2 is a known Gpa2GAP. Phosphodiesterases (Pde1 and Pde2) antagonize glucose signaling via enzymatic
inactivation of cAMP (conversion to AMP). The PKA tetramer is the regulatory target of cAMP. While bound to the kinase subunits (TPK), the
regulatory Bcy1 subunits keep PKA in an inactive state; cAMP activates the catalytic subunits by binding to Bcy1 subunits and promoting
dissociation of the complex (dashed arrow).

occur despite disruption of the classical secretory pathway that
normally mediates translocation from the endoplasmic reticu-
lum to the plasma membrane (92).
Additional signal transduction components appear to con-
tribute to glucose signaling by contacting adenylate cyclase
(Cyr1); such Cyr1 protein-protein interactions identified thus
far include those with (i) an N-terminal SH3 domain in the
RasGEF Cdc25 (237), (ii) the farnesylated Ras2 C terminus
(73, 74, 184, 199, 338, 355), (iii) the C terminus of the putative
cochaperonin Sgt1 (95), (iv) the N terminus of the ancillary
factor Srv2 (CAP) via coiled-coil formation (267), and (v) the
RasGAP Ira1, which mediates peripheral association of ade-
nylate cyclase with the yeast plasma membrane (241).
It seems likely that the sole purpose of the glucose-induced
spike in cAMP levels is to block the inhibitory effect of the
BCY1-encoded regulatory subunit on the catalytic subunits of
PKA, encoded redundantly by TPK1, TPK2, and TPK3; over-
expression of any of these three genes, or deletion of BCY1,
restores growth to ras1⌬ ras2⌬ strains (369). PKA is a het-
erotetramer consisting of two catalytic (Tpk) subunits and two
regulatory (Bcy1) subunits (Fig. 2); addition of regulatory sub-
units to catalytic subunits in vitro converts protein kinase ac-
tivity into a completely cAMP-dependent form (151, 177, 370).
Interestingly, the subcellular localization of PKA catalytic
and regulatory subunits appears to respond to glucose signal-
ing; Bcy1 is present in both the cytoplasm and nucleus in the
absence of glucose but is exclusively nuclear in its presence
(129, 130). Cross talk from the TOR (target of rapamycin)
pathway, another major set of nutrient-responsive signaling
components, may help to maintain PKA activity in part by
regulating nuclear translocation of Tpk1 (330). Although it has
yet to be demonstrated that the observed translocation of PKA
subunits between compartments plays an important role in
glucose signaling in yeast cells, targeting of PKA regulatory
substrates would appear to undergo a qualitative and/or quan-
titative shift in response to the appearance or disappearance of
258 SANTANGELO
the sugar. Further progress in this area is complicated by the
fact that signaling via each of the three different catalytic sub-
units of PKA (Tpk1, Tpk2, and Tpk3) results in a distinct
pattern of downstream gene expression readouts (309).
Although active PKA is thought to phosphorylate proteins
involved in transcription, energy metabolism, and cell cycle
progression (129), further study is required to identify the
exact targets and sequence of protein translocation and phos-
phorylation events that transmit the glucose regulatory signal
to the yeast nucleus. Significantly, mutations impairing specific
components of the RNA polymerase II transcriptional machin-
ery are synthetically lethal with the hyperactive Ras2Val19 allele
(157), and PKA can phosphorylate a component of the Srb
complex (Ssn2) both in vitro and in vivo (55). The latter may be
one of but a few Ras/cAMP/PKA-mediated modifications in
nuclear factors needed to accomplish the broad sweep of al-
terations to the yeast transcriptome upon glucose addition or
depletion.
The Ras/cAMP/PKA pathway has also been implicated in
aging (212, 216), thermotolerance (439), bud site selection,
actin repolarization (333), glycogen accumulation (342), stress
resistance (39, 407), and sporulation (39, 41); it may also reg-
ulate pseudohyphal differentiation (growth as chain-like mul-
ticellular filaments) in response to nutrient limitation. Each of
these interesting topics (see reference 411 for a recent review),
as well as the involvement in these processes of other nutrient-
stimulated kinases (e.g., Snf1 and TOR [45, 75, 196, 197, 401,
441]), GTPases (e.g., Gpa2 [277]), and transcription factors
(e.g., Msn2/Msn4 [30, 96, 112]), is outside the scope of this
review.
The Gpr1/Gpa2 pathway. Heterotrimeric G proteins are sig-
naling molecules composed of ␣, ␤, and ␥ subunits. They
represent a second class of factors that, like monomeric Ras
polypeptides, are capable of binding guanine nucleotides (Fig.
2). The G␣ subunit Gpa2 and its negatively acting regulator
(GAP) Rgs2 have been shown to participate in glucose signal-
ing in S. cerevisiae (190, 394). Gpa2 was originally identified by
screening a yeast genomic library with cDNA probes encoding
mammalian G␣ subunits (252), and the putative ␤ subunits
Gpb1 and Gpb2 were identified as interaction partners of
Gpa2 (135); no corresponding G␥ subunits involved in glucose
signaling have yet been identified (but see reference 135).
Whereas deletion of either GPA2 or RAS2 causes little or no
impairment of growth on glucose media, deletion of both
causes a severe synthetic growth defect (428). Removal of the
major cAMP phosphodiesterase in the cell (Pde2) restores
normal growth to gpa2⌬ ras2⌬ strains, suggesting that an in-
crease in cAMP levels bypasses the loss of both Gpa2 and Ras2
(428). Most importantly, as mentioned above, the transcrip-
tomic response to glucose is successfully mimicked in the ab-
sence of the sugar by turning on expression of either activated
Gpa2 or activated Ras2; the fact that this signaling is PKA
dependent confirms their redundant participation in the
cAMP-dependent branch of glucose signaling (408).
A two-hybrid protein interaction screen with GPA2 as the
bait led to the identification of the GPR1 gene, which encodes
a member of the G protein-coupled seven-transmembrane re-
ceptor superfamily (Fig. 2). Gpr1 is located on the yeast cell
surface (428). Genetic analysis strongly suggests that Gpa2 acts
downstream from Gpr1 in the same signaling pathway: the low
MICROBIOL. MOL. BIOL. REV.
growth rates of gpr1⌬ ras2⌬, gpa2⌬ ras2⌬, and gpa2⌬ gpr1⌬
ras2⌬ strains are essentially identical, and introduction of ei-
ther multicopy or activated GPA2 suppresses the defect of the
gpr1⌬ ras2⌬ strain (428). Deletion of GPR1 diminishes (al-
though does not eliminate) genome-wide transcriptional in-
duction and repression in response to glucose (408). The sim-
plest explanation for these data is that Gpr1 is the only
receptor coupled to Gpa2 and that it too contributes to acti-
vation of the cAMP pathway in response to glucose (190).
Although Gpa2 was originally thought to function upstream
of the Sch9 kinase (368, 428), it was subsequently found that
SCH9 deletion is synthetically lethal with gpr1⌬, gpa2⌬, or
ras2⌬, suggesting that Sch9 acts instead in the pseudohyphal
differentiation pathway that is parallel to both Gpr1/Gpa2 and
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Ras (217). Sch9 may nevertheless participate somehow in glu-
cose signaling, since (i) it is the yeast ortholog of a component
of the mammalian insulin response pathway (Aft/protein ki-
nase B), (ii) it shares similarity with PKA catalytic subunits,
(iii) its overexpression compensates for the loss of Ras func-
tion, and (iv) PKA activity is elevated in a sch9⌬ background
(72, 109).
Activation of Ras and Gpa2 by glucose. Since artificial acti-
vation of Ras and Gpa2 is sufficient to generate the glucose
response, and it seems unlikely that glucose interacts directly
with the G proteins themselves, how do Ras and Gpa2 become
activated in wild-type yeast cells exposed to the sugar? It is
convenient to separate potential answers to this question into
two categories: recognition of glucose by receptors on the outside
surface of the cell versus direct signaling of Gpa2 and Ras (or
their regulators) by intracellular glucose or its metabolites.
(i) Extracellular sensing. There are 18 known hexose trans-
porter genes in S. cerevisiae (HXT1 to HXT17 and GAL2).
Deletion of seven of these genes results in the failure to trans-
port or grow on glucose (308, 413). In this hxt1 to hxt7 null
background, constitutive expression of the GAL2-encoded ga-
lactose permease restores glucose-induced cAMP synthesis
(313). This suggests that the yeast hexose transporters do not
participate in glucose signaling but are required only for
transport.
The seven-transmembrane receptor Gpr1 may detect extra-
cellular glucose and thereby activate Gpa2, but it is not re-
quired to signal Ras; Gpr1 or Gpa2 deletion does not prevent
the glucose-induced increase in Ras2-GTP levels (66). In con-
trast, the Ras2-GTP increase is absent in a glucose phosphor-
ylation-deficient (hxk1 hxk2 glk1) strain (66). Thus, Ras ap-
pears to be activated by intracellular phosphorylated glucose
but not by extracellular glucose. A clear demonstration of
extracellular sensing by Gpr1 will require direct evidence, for
example, as suggested by recent mutagenic analysis (205), that
it interacts with glucose.
(ii) Intracellular sensing. If extracellular signaling does not
participate in Ras activation (66, 313), it will be particularly
important to understand how intracellular glucose triggers the
glucose response. The longstanding idea that glucose phos-
phorylation (in particular by the glucose-induced hexokinase
Hxk2; see below) and/or subsequent glycolytic reactions are
required to alter yeast gene expression in response to glucose
has been controversial (see references 20, 121, 244, and 314 for
reviews of this topic). Since repression occurs even when the
metabolic steps immediately following glucose phosphoryla-
VOL. 70, 2006
tion are reduced to less than 2% of wild-type levels, it seems
likely that nothing beyond the production of glucose-6-phos-
phate is required (317). Further, since cells can be tricked into
the full-blown glucose response by expressing activated Ras or
Gpa2, glucose phosphorylation must generate the signal
through the G proteins and/or through a redundant and as-
yet-obscure alternative pathway. A recent interesting sugges-
tion is that glucose phosphorylation increases Ras2-GTP levels
by inhibiting the Ira (RasGAP) proteins (66).
Although progress has been made, much more work is
needed to establish the precise mechanism(s) through which
Ras, Gpa2, and/or their regulatory GEFs and GAPs is signaled
by glucose. Intracellular acidification (316, 365) and energy
charge (the AMP/ATP ratio) (134, 244) are additional poten-
tial signaling mechanisms that require further testing. The
events that immediately follow activation of either G protein
are much clearer (Fig. 2). Activated Ras or Gpa2 can each
generate a spike in cAMP production by adenylate cyclase;
cAMP in turn releases PKA catalytic (Tpk) subunits from
inhibition by its regulatory (Bcy1) subunits.
Extracellular sensing by Snf3/Rgt2. The putative glucose
sensors Snf3 and Rgt2 are 60% identical to each other and, like
hexose transporters found in bacteria, plants, and mammals
(228, 259, 332), contain 12 predicted transmembrane-spanning
domains (272). Snf3 and Rgt2 do not appear to act as glucose
transporters but instead signal the presence of the sugar (118,
178, 182, 247, 273, 314). Since the transcriptional response of
Snf3/Rgt2 target genes (e.g., HXT genes encoding the glucose
transporters) is generated in the absence of glucose by expres-
sion of hyperactive Ras or Gpa2, the Snf3 and Rgt2 sensors
appear either to act upstream of Ras/cAMP/PKA or to play an
ancillary or redundant role in the initial detection of glucose.
This view is consistent with the possibility that glucose sensing
by Snf3/Rgt2 is required for maintenance of glucose induction
or repression for at least a subset of the transcriptome (182,
272). Further, it seems clear that the Snf3/Rgt2 regulatory
pathway helps to ensure that changes in gene expression are
commensurate with the glucose concentration in the environ-
ment, a mechanism that is likely to be particularly important in
nature.
As mentioned above for Gpr1, a clear demonstration of
extracellular sensing by Snf3 and Rgt2 will require direct evi-
dence that they interact with glucose. Intriguing hints along
these lines have already been uncovered. The V404I mutation
in Rgt2 appears to abolish glucose signaling; this residue is
orthologous to one in Hxt1 (F371) that is necessary for glucose
transport (247). V404 in Rgt2 may therefore be required for
glucose sensing because it helps to form the glucose binding
domain in the receptor. Similarly, dominant mutations in both
Snf3 (R229K) and Rgt2 (R231K) that cause constitutive sig-
naling, even in the absence of glucose, map to the putative
glucose binding pocket (272, 273). Progress has also been
made with respect to the elaboration of a mechanism for sub-
sequent signaling by Snf3 and Rgt2 across the plasma mem-
brane (see below).
SIGNAL RECEPTION: GLUCOSE REPRESSION
Direct sensing of extracellular glucose by yeast cells, rather
than intracellular sensing of its metabolic products, is a rela-
GLUCOSE SIGNALING IN S. CEREVISIAE 259
tively new concept. Further study of receptor-mediated signal-
ing in yeast may prove critical in understanding similar nutrient
sensors in mammalian cells (179). How PKA, once unleashed,
remodels the architecture of the yeast nucleus to produce the
ultimate transcriptomic consequences of glucose induction and
repression will be a central consideration of the remainder of
this review.
Most of the ⬃1,000 genes in S. cerevisiae that are transcrip-
tionally downshifted during growth on glucose can be sorted
into one of three groups: gluconeogenic genes, Krebs cycle/
respiratory genes, and genes involved in alternate carbon source
metabolism. This section will review known mechanisms through
which the glucose signal is received in the yeast nucleus and
modulates expression of glucose-repressed target genes.
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Involvement of the Hexokinase Hxk2
in the Glucose Response
The first, irreversible step in the intracellular metabolism of
glucose is C6 phosphorylation. Three enzymes (encoded by
HXK1, HXK2, and GLK1) can catalyze this reaction; of these,
only HXK2 is highly expressed in the presence of glucose (147).
HXK2 lesions (both point and null mutations) were long ago
shown to cause failures in glucose repression (99, 100, 104,
222). After much controversy, it is now deemed unlikely that
Hxk2 catalytic activity plays an important role in the intracel-
lular glucose signaling pathway (244). The surviving version
of this model postulates that, following the onset of the
phosphoryl transfer reaction, a stable transition intermediate
alters Hxk2 conformation and mediates its regulatory function
in altering target gene expression (20, 191). However, this
model fails to explain the fact that sugars metabolized in an
Hxk2-independent fashion can cause genome-wide transcrip-
tional repression comparable to that observed after the addi-
tion of glucose to wild-type cells or upon expression of acti-
vated Ras or Gpa2 (17, 214, 312, 397, 408).
Interestingly, approximately 14% of Hxk2 is nuclear in glu-
cose-grown cells (146). This discovery suggests an alternative
explanation for the regulatory involvement of this hexokinase
in the glucose response (244, 304). Hxk2 has been detected in
the nucleus by enzymatic assay, immunoblotting, and fluores-
cent visualization of a green fluorescent protein (GFP)-tagged
chimera, confirming controversial reports of nuclear hexoki-
nase that first appeared in the early 1960s (234, 340, 390). The
negatively acting DNA-bound glucose regulator Mig1 (see be-
low) appears to mediate nuclear localization of Hxk2; Mig1
and Hxk2 have been shown to interact via two-hybrid, immu-
noprecipitation, and glutathione S-transferase pull-down as-
says (2, 245). An interaction between Hxk2 and the Mediator
component Med8 has also been described, and the latter ap-
pears to bind directly to both positively and negatively acting
glucose regulatory elements in DNA (57, 80, 246). A previously
reported example of a metabolic enzyme that doubles as a
transcriptional regulator is the galactokinase Gal1, which both
phosphorylates galactose and appears to activate the transcrip-
tion factor Gal4 by binding to the Gal4 inhibitor Gal80 (436).
Despite these intriguing hints, contradictory results prevent
an unambiguous assignment of the Hxk2 function in glucose
regulation to the nuclear form of the protein. For example,
removal of a small N-terminal segment of Hxk2 (residues 7
260 SANTANGELO
through 16) in a putative nuclear localization sequence (Lys8-
Pro-Gln-Ala-Arg12) has been reported to abolish both Hxk2
nuclear localization and glucose repression of SUC2, HXK1,
and GLK1 without impairing hexokinase catalytic activity (146,
311). The exact opposite result (intact glucose signaling and
low catalytic activity), however, was obtained by others upon
deletion of an overlapping and slightly larger Hxk2 segment
(residues 1 through 15) (231). Likewise, the phosphorylatable
Ser14 residue in Hxk2 (193) is reported either to mediate (305)
or not to mediate (146, 231) glucose repression. Further anal-
ysis is needed to resolve these discrepancies. Most importantly,
proof of a regulatory role for nuclear Hxk2 awaits an unam-
biguous demonstration that its role in the glucose response
relies upon the relatively small fraction of the protein that
resides in the nucleus.
Snf1-Mediated Signal Transduction in Glucose
Repression and Derepression
The uncertainty surrounding the role of Hxk2 subcellular
localization and phosphorylation state in the glucose response
is particularly important to resolve because it represents one of
several potential connections between Ras/cAMP/PKA-depen-
dent events that occur early in the signal transduction cascade
and downstream modifications that have a direct impact on
target gene expression. Importantly, increasing the extracellu-
lar glucose concentration, or hyperactivation of PKA via bcy1
deletion, results in reduced Hxk2 phosphorylation, whereas
attenuation of PKA activity increases 32P labeling of Hxk2
(398). These data are consistent with a model in which Hxk2
dephosphorylation, which converts it from a monomer to a
dimer (305), somehow transduces the glucose signal to down-
stream effectors, eventually resulting in repression (and per-
haps also induction) of glucose-regulated genes. The nuclear
form of Hxk2 might accomplish this via its direct interaction
with Med8 and/or Mig1 (see above). Alternatively or addition-
ally, such an Hxk2 signal might be received by two additional
phosphoproteins that are well established as downstream com-
ponents in the glucose signal transduction pathway: the Reg1-
targeting subunit of the Glc7 phosphatase and the Snf1 kinase
(325).
Dueling Snf1 kinase and Glc7 phosphatase mediate glucose
regulation. SNF1 was first identified in screens for regulatory
factors in the glucose response (it was then named either CAT1
or CCR1) (62, 102, 440). SNF1 was also identified in a screen
for mutants that could ferment glucose but not sucrose (46).
Since inactivation of SNF1 also impairs utilization of galactose,
maltose, and nonfermentable carbon sources, soon after its
identification it was recognized as an important regulatory
gene mediating glucose derepression. The SNF1 gene was
cloned and found to encode a serine-threonine protein kinase
(51); the existing evidence also suggested a physical and func-
tional link to SNF4, another gene that had been identified in
the “sucrose nonfermenting” screen (49, 50, 259, 261). The snf4
and snf1 phenotypes are similar, including defective utilization
of the many carbon sources (e.g., sucrose, galactose, maltose,
raffinose, and lactate) that require expression of glucose-re-
pressed genes. Increased SNF1 dosage and SNF1 mutations
(e.g., the SNF1-G53R allele, which produces a hyperactive
kinase) can partially restore glucose derepression in the ab-
MICROBIOL. MOL. BIOL. REV.
sence of SNF4 (53, 108, 204). Since Snf4 also coimmunopre-
cipitates with Snf1 and is required for maximal Snf1 protein
kinase activity (in cells grown on a nonfermentable carbon
source) (52), it is a physically associated activator of the Snf1
kinase (108, 113). Like Glc7 (and perhaps Reg1; see below),
Snf1 appears to have a regulatory role in glycogen metabolism
that is somehow influenced by PKA signaling (see reference
119 for a review). While this apparent connection between the
signal transduction pathways governing glucose catabolism and
glycogen storage is intriguing, it remains poorly defined and
will not be considered further here.
Identification of a role in glucose repression for Glc7, the
yeast homolog of mammalian type I protein phosphatase (PP1)
(111), began with a selection for mutants defective in glucose
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repression of a target gene (SUC2, encoding invertase) (260).
All of the recovered mutations were recessive; two of the three
complementation groups found in this screen proved to be
allelic with HXK2 and REG1, respectively. The third group
identified a new locus (designated cid1, for constitutive inver-
tase derepression). Complementation of one of these muta-
tions (cid1-226, now designated glc7-T152K) (378) led to the
isolation of GLC7, a locus that was also identified indepen-
dently in a screen for glycogen-deficient mutants. Interestingly,
in addition to SNF1 (GLC2), other glc lesions were allelic with
IRA1 (GLC1), IRA2 (GLC4), and RAS2 (GLC5) (42), consis-
tent with numerous studies connecting Ras and Gpa2 signaling
with accumulation of the storage carbohydrates trehalose and
glycogen (40, 41, 67, 125, 190, 284, 330, 363). Further investi-
gation is needed to pursue this implicit regulatory linkage
between glucose catabolic pathways and carbohydrate storage.
Complicating matters further, in addition to glucose repres-
sion and carbohydrate accumulation, GLC7 phosphatase is
needed for a variety of other cellular functions in S. cerevisiae
(14, 350, 437), including normal progression through the G2/M
phase of the cell cycle (23, 24, 150, 159, 223, 288), actin orga-
nization (6, 54), translation (412), and sporulation (12, 42, 302,
357, 378, 380). Recent work has further expanded this list of
functions assigned to yeast PP1; it is also required for the
glucose-induced vacuolar degradation of fructose-1,6-bisphos-
phatase (76) and for normal Mex67-mediated export of mRNA
from the nucleus to the cytoplasm (127; see also references
381, 382, and 404).
Interestingly, isolated PP1 molecules exhibit little substrate
specificity and instead require regulatory subunits that alter the
conformation of the phosphatase and/or target it to its sub-
strates (65, 97). This targeting hypothesis is supported by the
Glc7 localization pattern, which suggests dynamic changes
throughout the yeast cell cycle (24). Glc7 binding proteins
specific to the following functions have been reported: glucose
repression (Reg1) (380), glycogen metabolism (Gac1 and Pig1)
(59, 353, 426), cell cycle progression (Reg2 and Sds22) (120,
149, 288), actin organization (Scd5) (54), and sporulation
(Gip1) (357, 380).
A short motif present in most known regulatory subunits
([RK]-X0-1-[VI]-X-[FW]) plays a critical role in the interaction
with a hydrophobic groove at the interface of two ␤-sheets in
PP1 (97, 403). Thus, multiple regulatory subunits appear to
compete for Glc7 binding in vivo; for example, Gac1 overex-
pression affects glucose repression (426). In addition to bind-
ing regulatory subunits, the hydrophobic groove may mediate
VOL. 70, 2006
changes in the structure and/or activity of the phosphatase. It
also now seems likely that many if not all targeting subunits
interact with more than one site on the PP1 surface (425). In
the two-hybrid assay the F468R mutation in Reg1 dramatically
reduces its interaction with Glc7; the PP1 binding motif that
contains this residue (RHIHF468) therefore appears to be one
of the moieties required for formation of the Reg1/Glc7 com-
plex (325). Importantly, Reg1 is the only regulatory subunit
known to participate in glucose repression.
The idea that Reg1 (first identified in reference 230 and in
an earlier screen as Hex2 [101]) mediates the Glc7 role in
glucose repression arose because (i) reg1 and glc7 alleles were
both isolated in the screen for mutants with impaired repres-
sion of SUC2 (260, 378) (see above), (b) a combination of
those defective alleles exhibited no synergy in relief from glu-
cose repression of SUC2, (iii) SNF1 deletion is epistatic to both
alleles, and (iv) Reg1 overexpression suppresses the repression
defect caused by glc7-T152K (379). Genetic and biochemical
experiments confirmed that Reg1 and Glc7 are linked both
physically and functionally (325, 379). The results of alanine-
scanning mutagenesis suggested that Reg1 interacts with at
least two distinct areas of the resolved PP1 structure (14).
Satisfyingly, one of the Glc7 surfaces specific to its role in
glucose repression is adjacent to Thr152 (14); the glc7-T152K
lesion had earlier been shown to impair Reg1-Glc7 interaction
(379).
A functional link between Reg1 and Snf1 was suspected long
ago, primarily because REG1 deletion results in derepression
of glucose-repressed genes and SNF1 deletion results in a
failure to derepress many (if not all) of those same genes. The
demonstration that Reg1 and Snf1 interact (218) left little
doubt that the Reg1-targeted Glc7 phosphatase and Snf4-
activated Snf1 kinase are indeed interconnected compo-
nents of the glucose signaling pathway (106, 120, 162, 174,
378, 379; see references 45, 121, and 178 for reviews) (Fig. 3).
Since then numerous additional participants in this regulatory
duel have been discovered. For example, three ancillary com-
ponents of the Snf1/Snf4 kinase complex (Sip1, Sip2, and Gal83)
strengthen Snf1/Snf4 association (175, 429, 430). Each of these
three proteins contains an Snf1 binding internal region and an
Snf4 binding C-terminal region (their N-terminal regions are
divergent); they therefore appear to bridge the interaction
between Snf1 and Snf4. By analogy with the heterotrimeric
mammalian Snf1 homolog, the AMP-activated protein kinase,
SNF1 encodes the yeast ␣ subunit, SNF4 encodes the ␥ subunit,
and SIP1, SIP2, and GAL83 redundantly encode the ␤ subunit
(136).
It was initially puzzling that little or no detectable phenotype
resulted from mutation of all three genes that encode the ␤
subunits of the Snf1 kinase complex (105, 106, 121, 175). How-
ever, the construction of true null alleles revealed that, as
expected, the sip1⌬ sip2⌬ gal83⌬ triple mutant does indeed
display an snf1 phenotype (331). Despite the observed redun-
dancy, the three ␤ subunits play distinct roles in vivo, in par-
ticular with respect to Snf1 substrate specificity (143, 144, 175,
213, 254, 331, 396, 397, 430).
Besides its role in the response to glucose limitation, Snf1
has also been implicated in several other processes, including
aging, thermotolerance, peroxisome biogenesis, filamentation,
invasive growth, biofilm formation, meiosis, and (like Glc7)
GLUCOSE SIGNALING IN S. CEREVISIAE 261
sporulation (8, 45, 137, 196, 197, 297, 401). Clearly more work
is needed before we will fully understand the respective rela-
tionships between the distinct forms of the Snf1 kinase com-
plex and each of these regulatory mechanisms. However,
Gal83 is likely to be a primary contributor to glucose regula-
tion by the Snf1 complex, since Gal83 is the most abundant ␤
subunit, it is the only ␤ subunit in the nucleus when cells are
grown on a nonfermentable carbon source, and Snf1/Gal83 is
the form responsible for most Snf1 kinase activity (144, 397).
Another trio of factors that mediate Snf1 function are the
redundantly acting Snf1 kinase kinases Sak1 (YER129W, for-
merly known as Pak1; the new name was chosen to avoid
confusion with Prk1 or p21-activated kinases), Tos1, and Elm1,
each of which shares sequence similarity with the human tumor
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suppressor and AMP-activated protein kinase LKB1 (155, 255,
354, 422). Removal of all three yeast activities confers an snf1
phenotype. A one-to-one correspondence between these three
upstream kinases and the distinct forms that contain each of
the three ␤ subunits has been ruled out (143). Since Sak1 is the
most important of the trio of Snf1 kinase kinases in activating
the Snf1/Gal83 form, it is likely also to be the most important
regulator of Snf1-dependent glucose regulation (143). This
conclusion is further supported by the observation that dele-
tion of SAK1 suppresses many of the Snf1-dependent pheno-
types observed in reg1⌬ cells (255).
Like Glc7 and its regulatory subunits, the Snf1 kinase ap-
pears to be localized by its ␤ subunits to distinct cellular sub-
compartments, thereby targeting it to different substrates (331,
397). In glucose-grown cells Snf1 is found exclusively in the
cytoplasm; following a shift to a nonfermentable carbon
source, Snf1 is targeted by Gal83 to the nucleus. The N termi-
nus of Gal83, which is not shared by the other two ␤ subunits
Sip1 and Sip2, is required for this function; the upstream ki-
nase Sak1 also controls Snf1 localization to the nucleus in the
absence of glucose (144, 397). Upstream events in glucose
signaling may also be involved, since it has been reported that
PKA regulates nucleocytoplasmic shuttling of Snf1/Sip1 (144).
If PKA also regulates shuttling of Snf1/Gal83, it appears to do
so redundantly with another signaling pathway.
With respect to subnuclear localization, three as-yet-uncon-
nected observations suggest the possibility that the Snf1 kinase
complex operates at least in part at the nuclear periphery: Snf1
is concentrated in nuclear envelope fractions prepared from
pyruvate-grown (but not glucose-grown) cells (B. Menon and
G. M. Santangelo, unpublished data), Glc7 has been impli-
cated in mRNA processing as a component of the cleavage/
polyadenylation complex (127, 256, 404), and Reg1 deletion
causes an RNA processing defect (381, 382). Further elabora-
tion of this potential connection with perinuclear phenomena
is needed and may provide critical information about the func-
tion and organization of the regulatory apparatus in the yeast
nucleus that responds to glucose (see below).
An overview of the regulatory duel between the Reg1/Glc7
phosphatase and the Snf1 kinase complex is presented in Fig.
3. Snf1 has two domains, an N-terminal kinase domain and a
C-terminal regulatory domain. In high concentrations of glu-
cose the regulatory domain remains bound to the catalytic
domain, maintaining Snf1 in an autoinhibited conformation
(labeled “inactive” in Fig. 3) (325). Upon depletion of glucose,
Snf4 counteracts autoinhibition of Snf1 by interacting with its
262 SANTANGELO MICROBIOL. MOL. BIOL. REV.

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FIG. 3. The opposing roles of Reg1/Glc7 phosphatase and the Snf1 kinase complex. The duel between Reg1/Glc7 and Snf1/Snf4/Gal83 turns
the Snf1 kinase on (ACTIVE) and off (INACTIVE) by determining whether the Snf1 regulatory domain (RD) binds to and autoinhibits its kinase
domain (KD). This switch plays a central role in determining the transcriptomic response to the presence or absence of glucose. The ␤ subunit
Gal83 acts as a scaffolding factor for the nuclear form of the Snf1 (␣) and Snf4 (␥) subunits of the kinase. Addition of glucose to yeast cells growing
on an alternative carbon source results in the dephosphorylation of active Snf1 kinase by Reg1/Glc7 (no. 1); this returns Snf1 to the autoinhibited
state (no. 2) and results in export of Snf1/Gal83 to the cytoplasm (not shown). Once glucose is depleted, Sak1 phosphorylates Snf1 (no. 3),
Snf1/Gal83 enters the nucleus (not shown), and Snf4 binds to the Snf1 regulatory domain, thereby releasing the catalytic domain (no. 4); Reg1 then
undergoes rapid Snf1-dependent phosphorylation (no. 6), which stabilizes the interaction between Snf1 and the Reg1/Glc7 phosphatase (no. 7) and
primes the latter to repress Snf1 anew should glucose reappear. Std1 interacts with the Snf1 catalytic domain and stimulates kinase activity (no.
5), although it is stoichiometrically underrepresented in Snf1 complexes. A dynamic equilibrium (purple arrows between no. 6 and 7), in which Glc7
appears to counteract Snf1 phosphorylation of Reg1 and promote its own dissociation from active kinase complexes, is at the heart of this
regulatory duel. Sip5 may stabilize the Reg1/Snf1 interaction in no. 6 (not shown). Hxk2 interacts with Reg1 (not shown), and Hxk2 may respond
to PKA signaling by dimerizing and mediating the switch in Glc7 phosphatase substrate selection (from Reg1 [no. 7] to Snf1 [no. 1]; see the text).

regulatory domain; deletion of the latter bypasses the require-
ment for SNF4 in derepression of glucose-repressed genes (52,
174, 204). Snf4 binding to Snf1 therefore produces an active,
open conformation of the complex (labeled “active” in Fig. 3)
(174). Phosphorylation of a conserved threonine (T210) in the
activation loop of Snf1 is essential for activation of the kinase;
the upstream kinase Sak1 has been shown to phosphorylate
this residue and is required for full Snf1 kinase activity (255).
Blocking phosphorylation at this position via a T210A muta-
tion impairs Snf4 binding to the regulatory domain and pre-
vents the release of Snf1 autoinhibition (174, 198, 218). The
T210A lesion also interferes with normal nuclear enrichment
of Snf1 after a shift from high to low glucose (144). Since Snf4
localization to the nucleus is essentially carbon source inde-
pendent, in glucose-grown cells nuclear Snf4 is apparently not
associated with other subunits of the Snf1 kinase complex
(397). Thus, Snf4 apparently does not contribute to the cyto-
plasmic roles of Snf1 that are distinct from its mediation of
glucose derepression.
Glucose repression involves Reg1/Glc7-facilitated conver-
sion of the kinase complex from the active to the autoinhibited
state, presumably via dephosphorylation of Snf1 (325). Reg1/
Glc7 appears to associate only with active kinase complexes,
since the catalytic domain of Snf1 (phosphorylated at T210) is
required for the interaction with Reg1 (218). Upon activation
in a reg1 or glc7-T152K background, the Snf1 complex becomes
VOL. 70, 2006
trapped in the active conformation. Overexpression of Reg1,
but not overexpression of the mutated form that fails to bind
Glc7 (ReglF468R; see above), interferes with the Snf1/Snf4 in-
teraction in low glucose (325). Sip5, the first protein shown to
bind to both Reg1/Glc7 and the Snf1 kinase complex, may
stabilize the interaction between them and thereby facilitate
glucose repression, since the two-hybrid interaction between
Reg1 and Snf1 is reduced threefold in a sip5⌬ mutant (326).
The critical regulatory interaction between Reg1 and the
Snf1 complex was presumed to occur in the nucleus, especially
since that is where active Snf1 is predominantly located prior
to being switched off and exported following the appearance of
glucose, and Glc7 is known to be largely nuclear in growing
cells (24, 437). However, in contrast with a previous report that
found Reg1 in the nucleus (265), fluorescently tagged Reg1
appears to be exclusively cytoplasmic (90, 91). To resolve this
discrepancy it was proposed that the activated form of Snf1
cycles rapidly between the nuclear and cytoplasmic compart-
ments, allowing inactivation by Reg1/Glc7 to occur in the cy-
toplasm following the appearance of glucose (91). This hypoth-
esis has not yet been tested, but it may explain the apparent
role of Bmh1 and Bmh2 in glucose-regulated gene expression
(168). Bmh1 and Bmh2 are the yeast homologs of the some-
what mysterious 14-3-3 proteins (33, 388), which may serve as
mediators of Reg1 function (90) and are known to respond to
Ras/PKA signaling (124, 232).
Additional information concerning the connection between
upstream glucose signaling events and the Glc7/Snf1 regula-
tory duel will be the next topic of discussion, followed by a
review of the downstream DNA-bound phosphoproteins that
are known Snf1 regulatory targets and that account for much
of the transcriptomic response to glucose in yeast cells.
Transmission of the Ras/cAMP-dependent glucose signal to
Reg1/Glc7 and Snf1/Snf4. Although the regulatory duel be-
tween Snf1 kinase and Glc7 phosphatase has now largely been
explained at a molecular level, the input by glucose signaling
that shifts the balance in favor of the closed, inactive form of
the kinase remains poorly characterized. A proposal that Snf1
responds to the AMP/ATP ratio (421), which drops dramati-
cally upon removal of glucose (7, 421), has been difficult to
substantiate, since Snf1 kinase activity does not respond to
these nucleotides in vitro (136). In contrast, the ample evi-
dence that PKA and Snf1 act antagonistically in affecting a
similar set of cellular functions (7, 164, 366) is reinforced by
the similarity of the transcriptome-wide response of Snf1 target
genes following either the addition of glucose or the expression
of activated G proteins in the absence of glucose (408).
Sak1, the recently identified upstream activator of Snf1 that
regulates both Snf1 kinase activity and its nuclear localization
(144, 255), is an obvious potential intermediary between PKA
and Snf1 (question mark in Fig. 3). If the gap between the
earliest events in glucose signaling and Sak1 could be bridged,
it would represent a complete chain of causality between glu-
cose sensing at the cellular periphery and the response of
DNA-bound regulators in the nucleus. Not surprisingly, how-
ever, given that its role as an Snf1 activator was only recently
uncovered, little is yet known about regulation of Sak1 and
whether or not the PKA pathway might be involved.
GLUCOSE SIGNALING IN S. CEREVISIAE 263
Equally mysterious is the apparent capacity of the glucose
signal to change the target of Glc7 phosphatase from Reg1
to Snf1 (no. 7 and 1 in Fig. 3, respectively), which in the
absence of Snf1 phosphorylation (no. 3) traps Snf1 in the
autoinhibited inactive state. Interestingly, PKA signal trans-
duction might alter Glc7 targeting through the negatively
acting regulator Hxk2. As mentioned above, PKA signaling
appears to cause reduced phosphorylation of Hxk2, which
favors its dimeric form; the phosphatase that dephosphory-
lates Hxk2 in response to glucose is known to be Reg1/Glc7
(4, 305, 398). Hxk2 (presumably its underphosphorylated
dimeric form) in turn interferes with dephosphorylation of
Reg1 by Glc7 (325). Since only the phosphorylated form of
Reg1 promotes dissociation of Snf4 from Snf1 and inactiva-
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tion of the kinase, the PKA-mediated transition from mo-
nomeric to dimeric Hxk2 is potentially a direct glucose trig-
ger that stabilizes the repressing form of Reg1/Glc7 and
thereby inactivates Snf1. Reg1 and Hxk2 were reported to
interact as predicted by this model (325). This is further
supported by a wealth of additional data: Reg1 overexpres-
sion suppresses the glucose repression defect of an hxk2⌬
mutant (325), the association between Reg1 and Glc7 is
unaffected by removal of Hxk2, and the Snf1-Snf4 interac-
tion is glucose insensitive in the absence of Hxk2 (174).
A near-complete chain of causality describing the glucose
response can thus be stated as follows (Fig. 3): early events
in glucose signaling stimulate PKA to inhibit phosphoryla-
tion of Hxk2, thereby targeting it to Reg1/Glc7, where Hxk2
is dephosphorylated, dimerizes, and blocks dephosphoryla-
tion of Reg1 by Glc7; Glc7 then switches targets and inac-
tivates the Snf1 kinase, which can no longer phosphorylate
its DNA-bound substrates, resulting in altered expression of
the relevant target genes. Ambiguity unfortunately accom-
panies even this parsimonious view of the glucose regulatory
cascade, since the relationship between subcellular distribu-
tion and function awaits clarification for several of the fac-
tors involved (most notably Hxk2 and Reg1).
DNA-bound repressors controlled by Snf1. Several down-
stream repressors are known to be phosphorylated and inacti-
vated by the Snf1 kinase in the absence of glucose. The first of
these to be discovered was Mig1, originally identified as a
multicopy inhibitor of GAL gene expression (257). Deletion of
the MIG1 gene relieves glucose repression of numerous target
genes (115, 131, 180, 189, 257, 258, 335, 336, 406), and its
product is thought to interact with the intergenic regions of at
least 90 different genes in vivo (221, 251). Mig1 is presumed to
function downstream of Snf1, because deletion of MIG1 sup-
presses snf1 defects in glucose derepression (180, 386).
Mig1 is a Cys2His2 zinc finger protein that binds to a GC-rich
core sequence (219). The consensus Mig1 binding site deter-
mined by in vitro selection is 5⬘-ATAAAATGCGGGGAA-3⬘
(221). At the time of its discovery, other zinc finger proteins
were known to be capable of functioning as either activators or
repressors, depending upon the chromosomal and cellular
context (207). This was therefore also considered a possibility
for Mig1 (257), a suggestion that later proved to be correct:
both Mig1 and the related Cys2His2 zinc finger-containing
repressor Mig3 (Yer028) can also function as activators (220,
264 SANTANGELO
221, 303, 376, 423). Although this has complicated the
interpretation of Mig1 function (37, 160, 189, 376, 384, 386,
423), clearly the primary physiological role of Mig1 seems to be
that of a negative regulator of glucose-repressed genes (e.g.,
SUC2 and GAL1).
Interestingly, the Mig1 N-terminal zinc fingers are very sim-
ilar to those in the C terminus of WT1 (257), a human tumor
suppressor that collaborates with p53 to repress transcription
and (like p53) also activates transcription (133, 224, 235, 248,
264, 268, 306, 348). Mig1 and WT1 are both phosphoproteins,
and PKA phosphorylation of WT1 appears to make an impor-
tant contribution to its repressor function (323); the signifi-
cance of a potential PKA target site found in the internal
regulatory region of Mig1 is not yet known (257, 270).
Glucose-dependent repression by a LexA-Mig1 fusion is
readily detected by a heterologous reporter gene with up-
stream LexA operator sites, suggesting that Mig1 can repress
transcription without the assistance of other promoter-bound
factors (376, 377). Analysis of LexA-Mig1 repression also led
to the discovery that the Mig1 polypeptide, which has a pre-
dicted molecular mass of 55 kDa (504 residues), is phosphor-
ylated to different extents in glucose-repressed and dere-
pressed cells and might be a downstream target of Snf1 kinase
(87, 376). Indeed, three consensus Snf1 kinase sites (Ser278,
Ser311, and Ser381) map within a region of Mig1 required for
glucose regulation (77, 87, 269). All three of these sites, and a
fourth one that matches the Snf1 consensus imperfectly
(Ser222), are phosphorylated by Snf1 in vitro (343). Mutation
of these serine residues to alanine, including a Mig1 mutant
in which all four residues were mutated (S222A⫹S278A⫹
S311A⫹S381A), impaired but did not eliminate Mig1 phos-
phorylation and glucose repression (377). Nevertheless, in vivo
phosphorylation of Mig1 is dramatically reduced in an snf1
mutant, and immunoprecipitated Snf1 (but not the kinase-
dead Snf1-K84R) phosphorylates coprecipitated Mig1. Also,
as expected based upon their capacity to mediate glucose re-
pression by inhibiting Snf1 kinase activity, deletion of either
REG1 or HXK2 results in Mig1 hyperphosphorylation under
repressing conditions (377). Taken together, the simplest in-
terpretation of these data is that phosphorylation of Mig1 by
Snf1 is at least partly responsible for inactivation of Mig1
repressor function.
Deletions that map within an internal region containing
most of the Snf1 phosphorylation sites (residues 261 to 400)
converts Mig1 into a constitutive repressor that is not inacti-
vated when glucose is depleted (270). Interestingly, deletions
in Mig1 that remove all or part of the internal region from
residue 261 to 400 cause it to persist in the nucleus in the
absence of glucose, whereas under the same conditions wild-
type Mig1 is largely exported to the cytoplasm (87). Fusion of
Mig1 residues 261 to 400 to a GFP–␤-galactosidase chimera
confers glucose-regulated nuclear import and export upon the
resulting fusion protein, and its import in the presence of
glucose requires both REG1 and HXK2. In glycerol-grown cells
Mig1 becomes increasingly nuclear as more Snf1 kinase sites
are removed (86). Msn5, an importin ␤ homolog originally
identified due to its suppression of an snf1 mutation when
overexpressed (107), interacts with Mig1 and mediates its nu-
MICROBIOL. MOL. BIOL. REV.
clear export in response to glucose removal (86). These and
other data suggest that Snf1 phosphorylation of Mig1 inacti-
vates it by changing its subcellular localization.
According to this Mig1 nucleocytoplasmic shuttling hypoth-
esis, Hxk2- and Reg1/Glc7-dependent inactivation of Snf1 in
the presence of glucose results in hypophosphorylation of Mig1,
which causes it to relocate rapidly to the nucleus; subsequent
binding of Mig1 to its recognition sites upstream from glucose-
regulated genes mediates transcriptional repression (86, 87).
Although this model is attractive, it is difficult to reconcile with
two strikingly contrasting results. First, the Mig1 target gene
GAL1 is derepressed normally in an msn5 mutant grown on
glycerol, despite the constitutive presence of Mig1 in the nu-
cleus (86). Second, Mig1 remains bound to the GAL1 pro-
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moter in vivo under these same derepressing conditions (278).
Both of these results suggest that Mig1 transcriptional repres-
sion of target genes is regulated via a mechanism other than
nuclear export and that the key function of Snf1 phosphoryla-
tion in relieving Mig1-dependent glucose repression is to in-
activate the relatively small amount of Mig1 that remains in the
nucleus and is bound upstream of target genes in derepressed
cells (87, 270). How this is accomplished remains obscure.
Mig3, Nrg1, and Nrg2 are three additional Snf1-regulated
repressors in S. cerevisiae. Mig3 is somewhat mysterious; it was
identified because it contains Cys2His2 zinc fingers that are
very similar to those of Mig1 and Mig2 (26, 220). Several
additional results seem to suggest that Mig3, like Mig1 but not
Mig2, is an Snf1-controlled, DNA-bound glucose regulator
(182, 221). It binds to the Mig1 binding sites upstream from
SUC2, and a LexA-Mig3 chimera functions as a glucose-de-
pendent repressor of reporter gene expression when bound to
upstream LexA operators. When cells are shifted from glucose
to galactose, Mig3 is extensively phosphorylated (at least in
part by Snf1) and rapidly subjected to Snf1-dependent prote-
olysis (94). Nevertheless, physiologically significant regulation
of target genes by Mig3 is yet to be demonstrated; in wild-type
cells under standard conditions, it seems unlikely to be more
than a minor regulator of glucose-responsive gene expression
(220, 221). Recently the MIG3 gene was also isolated in a
screen for multicopy suppressors of Rad53-GFP toxicity, but
the relationship between Mig3 function and the DNA damage
response awaits further clarification (94). It is hoped that tran-
scriptomic analysis of the effects of an as-yet-untested environ-
mental condition or genetic background will eventually reveal
the Mig3 role in glucose regulation and explain the results
obtained to date.
Nrg1 and Nrg2 contain Cys2His2 zinc fingers that are very
similar both to each other and to those in Mig1, Mig2, and
Mig3 (400). Nrg1 was first identified in two separate screens
for factors mediating repression of glucose-regulated genes (1,
282), and Nrg2 was discovered because of its two-hybrid inter-
action with Snf1 (400). Outside of their DNA binding domains
Nrg1 and Nrg2 share only 27% identity, and this is thought to
account for their somewhat distinct regulatory roles in glucose
repression, filamentous invasive growth, and biofilm formation
(18, 196, 282, 400, 438). In the absence of glucose, neither
factor is degraded, nor is their capacity to bind target sites in
vivo impaired. Both Nrg1 and Nrg2 exhibit glucose-dependent
repression of a heterologous reporter gene; they are also both
capable of interacting with Snf1 kinase, but (unlike Mig1 and
VOL. 70, 2006
Mig3) neither appears to be phosphorylated by it (18, 400).
Although Snf1 appears to modulate Nrg2 levels and is clearly
required for normal Nrg1 function, the regulatory relationship
between these factors is complex and in need of further study.
Interestingly, like Mig1 and Mig3 (see above), Nrg1 can func-
tion as an activator in some circumstances (18).
DNA-bound activators controlled by Snf1. The Snf1 protein
kinase also regulates a number of positively acting transcrip-
tion factors required for the utilization of nonfermentable car-
bon sources. Two of these factors, Cat8 and Sip4, both contain
zinc finger DNA binding domains similar to that in Gal4 (a C6
zinc cluster) (145, 206) and bind specifically to a set of carbon
source responsive elements (CSRE) under derepressing con-
ditions (300, 395). Cat8 and Sip4 are closely related structurally
and appear to have slightly different affinities for variants of the
CSRE sequence (319). Although Sip4-dependent transcrip-
tional activation has been shown to require phosphorylation of
Sip4 by Snf1 kinase, removal of Sip4 has little or no effect on
CSRE-regulated genes (141, 145, 206, 299). Also, unlike dele-
tion of CAT8, which causes defective growth on nonferment-
able carbon sources, deletion of SIP4 results in no obvious
phenotype (206).
Cat8 regulates the expression of a wide array of genes in-
volved in the metabolism of nonfermentable carbon sources,
including genes necessary for ethanol utilization (e.g., ACS1
and ACR1/YJR095W) (28, 192), gluconeogenesis (141, 145),
the glyoxylate cycle (141), lactate utilization (JEN1) (27), and
isocitrate metabolism (IDP2) (27); Cat8 also regulates expres-
sion of SIP4 (141, 395). Cat8 activity is regulated on two levels:
its expression is Mig1 repressed (145, 257), and its capacity to
activate transcription requires a functional Snf1 kinase (303).
Snf1 phosphorylates Cat8 in ethanol-grown cells (56, 303);
following the addition of glucose, it is dephosphorylated in a
Glc7-independent manner (303). Interestingly, constitutively
expressed Cat8 fused to the Ino2 activation domain bypasses
the need for a functional Snf1 in cells growing on ethanol
(300).
Cat8 works together with another Snf1-regulated transcrip-
tional activator, Adr1, for maximal expression of a small group
of shared target genes (including ADH2, ACS1, and ALD6)
under derepressing conditions (25, 98, 192, 356, 405, 432). Like
the Mig1, Mig3, Nrg1, and Nrg2 repressors, Adr1 has a
Cys2His2-type DNA binding domain (283), and its function
requires Snf1 kinase (84), although the mechanism of Adr1
regulation remains unclear. It has been suggested that Snf1
and Reg1/Glc7 contribute to regulation of Adr1 by affecting its
binding to promoters of target genes. Snf1 promotes Adr1
binding under derepressing conditions, while Reg1/Glc7 inhib-
its Adr1 binding to promoters in the presence of glucose (91,
433); it is currently unknown whether Adr1 is a direct target of
Snf1 and Reg1/Glc7 or whether this effect occurs through
intermediary factors. Adr1 activity has also been reported to be
negatively regulated by PKA (60) in a manner independent of
its DNA binding (364).
SIGNAL RECEPTION: GLUCOSE INDUCTION
The connection between PKA function and up-regulation of
the ⬃1,000 glucose-induced genes is even more mysterious
than the mechanisms discussed above that control the ⬃1,000
GLUCOSE SIGNALING IN S. CEREVISIAE 265
genes whose expression is repressed in the presence of glucose.
Our clearest picture is of glucose induction by the Snf3/Rgt2
sensing mechanism, a pathway that appears to operate in a
largely PKA-independent fashion and (at minimum) contrib-
utes the critical regulatory trim that allows S. cerevisiae to grow
well on a broad range of glucose concentrations (from micro-
molar to molar concentrations) (272). The integral plasma
membrane proteins Snf3 and Rgt2 mediate both transcrip-
tional repression and derepression of four of the genes that
encode glucose transporters (HXT1 to HXT4). This pathway
establishes a regulatory link between glucose concentration
and expression of the transporters, and it operates in a largely
Snf1-independent fashion (for reviews, see references 179 and
272). Snf3 and Rgt2 are putative glucose sensors that appear to
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act redundantly with the Ras2/Gpa2/PKA pathway, since the
latter seems sufficient for glucose signaling through both the
Snf1-dependent and Snf1-independent branches (408) (see
above). Interestingly, however, like activating mutations in
RAS2 and GPA2, at least part of the glucose signal can be at
least partially mimicked in the absence of glucose via dominant
mutations in SNF3 or RGT2 (228, 272, 273). This may mean
that the Snf3/Rgt2 regulatory pathway, in addition to modu-
lating expression of key glucose transporters, signals PKA or a
PKA-independent glucose response pathway and thus aug-
ments or tailors the transcriptomic response beyond its well-
established effect on transporter genes.
Snf3/Rgt2 Signaling of the Rgt1 Repressor Complex
Upon transmission to the cytoplasmic side of the plasma
membrane, the Snf3/Rgt2-mediated glucose signal appears to
operate through YCK1 and its 77% identical paralog, YCK2, an
essential gene pair encoding casein kinase (Fig. 4) (310). Like
Ras (see above), Yck1 and Yck2 are tethered to the membrane
via palmitate moieties attached to C-terminal Cys-Cys se-
quences (9, 318). Membrane anchoring of the Yck proteins is
thought to facilitate an interaction with Snf3 and Rgt2 that
activates the kinases following the glucose-induced conforma-
tion change in the sensors; Yck1 has been shown to interact
with Rgt2 in vivo (179, 247). The targets of activated Yck
kinases in this pathway are Std1 and Mth1 (247), the corepres-
sors that interact with the Rgt1 repressor; the latter is a C6 zinc
cluster protein that binds directly to DNA sites upstream from
target genes (122, 163, 202, 272, 289, 332). Mutations in Rgt1
restore HXT gene expression and were originally isolated via
suppression of defective glucose regulation in the snf3⌬ and
grr1⌬ backgrounds (106, 227). Note that the Rgt1 repressor
blocks transcription of glucose-induced genes, unlike the Mig
and Nrg repressors, which block transcription of glucose-re-
pressed genes (see above). Thus, the Mig and Nrg proteins act
as repressors only in the presence of glucose, and Rgt1 acts as
a repressor only when glucose is absent (Fig. 4).
The large (⬎200-residue) cytoplasmic C-terminal tails of
Snf3 and Rgt2 are an important feature of this signaling path-
way. Deletion of the tail domains impairs Snf3- and Rgt2-
dependent gene regulation in response to glucose, and fusing
the tail to Hxt1 or Hxt2 complements those defects, as does
expression of the Snf3 tail domain by itself (69, 89, 228, 247,
272, 274). Although they were originally thought to play an
important role in receiving the glucose signal, recent evidence
266 SANTANGELO MICROBIOL. MOL. BIOL. REV.

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FIG. 4. The Snf3/Rgt2 signaling pathway. Transcription of hexose transporter genes (HXT) is repressed by Rgt1 in the absence of glucose; in
contrast, Mig1 represses transcription of its target genes in the presence of glucose and cross-regulates the Snf3/Rgt2 pathway as shown. Relief
from the repressor function of Rgt1 occurs via glucose signaling of the Snf3/Rgt2 sensors, which stimulate phosphorylation of Mth1 and Std1 by
Yck kinases; the C-terminal tails of Snf3 and Rgt2 also appear to facilitate this event by interacting with both the kinases and their substrates. The
Yck polypeptides are tethered to the plasma membrane via palmitate (red squiggles). Yck-phosphorylated Mth1 and Std1 are subjected to
SCFGrr1-mediated ubiquitination and degradation by the proteasome. This releases Rgt1 from its upstream DNA binding sites and results in
derepression of downstream HXT target genes. Removal of Mth1 and Std1 converts Rgt1 into a transcriptional activator that may stimulate HXT
expression in the absence of specific DNA binding activity.

suggests instead that a dynamic interaction with Mth1 and Std1
(201, 332) is the important function of the Snf3 and Rgt2
C-terminal tails in glucose signaling (247).
The membrane anchoring of Mth1 and Std1 by the cytoplas-
mic tails is thought to mediate phosphorylation of these Rgt1
corepressors by Snf3/Rgt2-associated Yck kinases (Fig. 4)
(247). Both Std1 and Mth1 can be phosphorylated by affinity-
purified Yck1 in vitro, and membrane fractions of crude ex-
tracts yield maximal Mth1 phosphorylation; mutant forms of
Yck kinase were used to demonstrate that the production of
phosphoforms of these regulators is Yck dependent (247). The
likely site of Yck phosphorylation is a region conserved in both
Std1 (residues 129 to 147) and Mth1 (residues 118 to 136),
each of which contains several matches with the consensus
target sequence of casein kinase I (SXXS) (247).
Once Std1 and Mth1 are phosphorylated by the Yck kinases,
they are degraded via a Grr1-dependent mechanism (Fig. 4)
(117, 179, 247). Mutations in GRR1 were shown long ago to
impair the regulatory response to glucose (11) and have since
been associated with a broad array of phenotypes, including
cell elongation, decreased divalent cation transport, defects in
sporulation, and slow growth or lethality in combination with
defective amino acid biosynthetic pathways (21, 114, 158, 215,
427, 431).
Interestingly, the F-box motif of Grr1, which mediates its
interaction with Skp1 (187), may explain the pleiotropic phe-
notype of grr1⌬ cells (10, 209). Skp1 is a component of several
structurally distinct but functionally related ubiquitin ligase
complexes that target a wide variety of regulators to the 26S
proteasome for degradation (for a review, see reference 414).
These complexes are termed SCF to indicate their two com-
mon components, Skp1 and the cullin Cdc53, and a third ex-
changeable component, the F-box protein. In S. cerevisiae a
total of 21 F-box proteins have been identified by sequence
VOL. 70, 2006
alignment (414). Further analysis is urgently needed, since
most of these factors have neither been verified as SCF com-
ponents nor characterized as to their function, and each bona
fide SCF subunit is expected to confer a distinct substrate
specificity upon its respective complex. Like Grr1, any one of
these F-box proteins could contribute to nutrient signaling by
targeting kinase substrates in response to the appearance or
disappearance of glucose.
Two F-box proteins that target cell cycle regulators for deg-
radation were first identified as a result of their important roles
in cell cycle progression: Cdc4, which targets the cyclin-depen-
dent kinase inhibitor Sic1, and Grr1, which (long after its
discovery as a regulator of the glucose response) was found to
target the G1 cyclins Cln1 and Cln2 (16, 110, 158, 209, 341, 393,
414). Grr1 was shown subsequently to also target Gic2, a
Cdc42 effector that mediates actin polarization at bud emer-
gence (170, 414). A breakthrough in understanding the initially
puzzling GRR1 contribution to the glucose response (11, 209,
385, 387) came with the discovery that SCFGrr1, in addition to
targeting the aforementioned cell cycle regulators, mediates
the ubiquitination and degradation of the Rgt1 corepressors
Std1 and Mth1 (117, 209, 347).
Grr1-mediated ubiquitination and degradation of Mth1 and
Std1 appear to require, in addition to the Skp1 interaction with
the Grr1 F box, an LRR domain comprised of 12 leucine-rich
repeats that form the substrate-targeting domain in Grr1 (158,
187). This is consistent with our knowledge of structure-func-
tion relationships in other F-box proteins, which invariably
possess a second motif that mediates substrate targeting (414).
For example, in Cdc4 a WD40 repeat domain is sufficient for
high-affinity interaction with its substrates (253).
Degradation of Mth1 in glucose-grown cells has been shown
to require both phosphorylation by Yck kinase (247) and the
LRR domain of Grr1, although Grr1 residues identified as
essential for Cln2 interaction appear to be distinct from those
required for interaction with Mth1 (117, 158, 347). No infor-
mation is yet available regarding the structural requirements of
the Grr1-Std1 interaction; this will likely be more difficult to
determine, since Std1 apparently does not disappear as com-
pletely as Mth1 in the presence of glucose (182).
In the absence of glucose Rgt1 binds to a consensus sequence
(5⬘-CGGANNA-3⬘) (186) found in multiple copies upstream of
the HXT target genes (250, 275). Transcriptional repression by
Rgt1 requires Mth1, which causes a conformation change that
allows Rgt1 to bind to its recognition sites in DNA (117, 202,
289). Std1 also interacts with Rgt1 in the absence of glucose
(289, 372), although it does not regulate the Rgt1 DNA bind-
ing activity (179). More work is needed to determine the
contribution of Std1 to Rgt1-mediated repression in the pres-
ence of glucose; an interesting possibility is that its interaction
with Rgt1 shifts the activator/repressor equilibrium (see below)
in favor of repressor function (289). Elimination of both Mth1
and Std1 appears to be required for maximal derepression of
Rgt1 target genes (202).
The central events in the Snf3/Rgt2 pathway, from glucose
signal generation at the plasma membrane to signal reception
by a DNA-bound repressor (179, 247), are depicted in Fig. 4.
As identified by global profiling (182), Snf3/Rgt2 signaling also
initiates feedback and feedforward regulatory loops that are
intertwined with the Snf1-dependent pathway. The Snf3/Rgt2
GLUCOSE SIGNALING IN S. CEREVISIAE 267
contribution to these regulatory loops involve three zinc finger-
containing repressors, Mig2, Mig3, and Rgt1, as well as the
Rgt1 corepressors Std1 and Mth1. For example, glucose sig-
naling through Snf3/Rgt2 induces expression of the MIG2-
encoded repressor, and in the absence of glucose Std1 binds to
and activates Snf1 kinase (Fig. 3) (see above). The Snf1-Mig1
pathway in turn represses expression of Snf3 and Mth1. Im-
portantly, despite these links to Snf1 kinase activity, signaling
by Snf3/Rgt2 does appear to operate as an independent glu-
cose response pathway (Fig. 4) (179, 182, 228, 272, 273). Thus,
Snf3 and Rgt2 initiate a component of the glucose response
that overlaps at least partially with both the PKA pathway and
its Snf1 kinase branch but that can also operate independently
of either.
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An important remaining aspect of this glucose regulatory
pathway that awaits clarification is the apparent capacity of
Rgt1, under conditions (high glucose concentration) in which it
no longer interacts with its recognition sites in DNA, to reverse
roles and function as an activator of HXT transcription and of
a heterologous reporter gene (186, 250, 271, 275) (however,
see also reference 117). Although its functional significance
remains unclear, transcriptional activation by Rgt1 requires
the glucose sensors Snf3 and Rgt2 and the F-box protein Grr1
(275).
The Cell Cycle Connection
Eukaryotic cells grow and divide at maximal rates only when
glucose is freely available. This requires sophisticated regula-
tory coordination between the metabolic engine of growth and
the wide variety of structural events required for cellular re-
duplication. With respect to glucose signaling it has long
seemed likely that there is a connection with the essential
cyclin-dependent kinase Cdc28; the latter acts in concert with
the G1 cyclins Cln1 to -3 at the primary gating event (Start) in
the cell division cycle (3, 116, 132, 165, 262, 263, 276, 285, 286,
321, 371, 416, 424; see references 83, 365, and 389 for reviews).
Unfortunately many of the critical relationships between the
growth and cell cycles have resisted elucidation. The slow
progress on this front is evident when one considers that Hart-
well first codified the basic questions over 30 years ago (138):
how does macromolecular synthesis communicate with the
CDC28 gene product, and how are all of these diverse inputs
(e.g., the pathways for carbon, nitrogen, sulfur, phosphorus,
and potassium assimilation) integrated at Start?
Two mechanisms of apparent coordination between glucose
signaling and cell cycle progression seem particularly worthy of
further attention. The first involves Grr1, the aforementioned
F-box protein that both relieves glucose repression as a com-
ponent of the Snf3/Rgt2 pathway and regulates Cln-dependent
Cdc28 function (209). Little is yet known about how Grr1
might integrate glucose signaling with cell cycle regulation, but
it now seems clear that it responds directly to glucose sensing
by Snf3 and Rgt2 at the plasma membrane. Second is the PKA
pathway, which has long been considered a general regulator
of cell growth in any carbon source and as such is thought to
participate in the dramatic increase in the rate of cell division
upon the appearance of fermentable sugars, including glucose.
As discussed above, many components of the PKA pathway
268 SANTANGELO
that were originally identified in connection with their role in
glucose signaling have now been thoroughly characterized.
Progress has also been made in understanding the ultimate
recipients of the glucose response in the yeast nucleus; PKA
signaling increases transcription of Rap1 target genes and ap-
pears to operate through the newly identified Rap1 coregula-
tors Fhl1/Ifh1 as well as the Rap1/Gcr1/Gcr2 transcriptional
activation assemblage (81, 83, 188, 320, 328, 402, 416). Target
genes activated by Rap1 fall into two main groups, glycolytic
and ribosomal protein (RP) genes (211). Not surprisingly,
these are the genes most abundantly transcribed by RNA poly-
merase II in S. cerevisiae cultures growing rapidly on glucose;
26 of the 30 most highly expressed transcription units are in
one of these two groups (392). Overall the Rap1 activation
mechanism(s) accounts for 60 to 75% of RNA polymerase II
transcription in rapidly growing cells (324, 410).
Transcriptional Induction of Glycolytic and
Ribosomal Protein Genes
Rap1 is an essential DNA binding protein required for both
transcriptional repression and activation of target genes (128,
339); interestingly, it also binds to telomeres and negatively
regulates telomere length (for a review, see reference 344).
The promoters of most genes encoding glycolytic enzymes
or ribosomal proteins contain sites occupied by Rap1 in vivo
(211). The Rap1 site appears to mediate the response of
these genes to the appearance or disappearance of glucose;
for example, their expression is coordinately down-regu-
lated upon depletion of glucose at the diauxic shift (85). The
PKA and TOR signaling pathways are thought to regulate
this response of Rap1-activated genes to nutritional status
(328, 402, 410, 441).
Recent reports suggest that the PKA and TOR pathways
intersect with respect to their shared role in stimulating RP
expression. The transcription factors Sfp1, Fhl1, Ifh1, and Crf1
appear to be key downstream targets of this signaling in the
yeast nucleus, and various unified models suggest how PKA
and TOR signaling might intersect to regulate cell cycle pro-
gression by controlling the rate of ribosome production (181,
226, 292). Although additional work is needed to clarify the
roles of these newly identified transcriptional regulators, to-
gether they appear to comprise the downstream targets of
nutrient sensing through the TOR pathway and thus are the
most likely recipients of signaling by the anticancer agent rapa-
mycin. In contrast, the Rap1 coactivator Gcr1 appears to re-
spond only to PKA; gcr1⌬ cells exhibit no alteration in rapa-
mycin sensitivity or rapamycin-induced down-regulation of RP
gene expression (S. J. Deminoff, K. A. Willis, and G. M. San-
tangelo, unpublished data). Like Fhl1/Ifh1, Gcr1 makes an
important contribution to nutrient sensing, since its removal
causes a long delay in the glucose response (as measured by
upshift of RP gene transcription, polysome formation, trans-
lation rate, and growth rate [416; see below]).
Transcriptional activation by Rap1 was shown long ago to
exhibit sensitivity to disruption of GCR1 (81, 324, 435). Ge-
nome-wide analysis has now demonstrated for the entire ge-
nome that genes with a Rap1 binding site in their promoter are
also Gcr1 target genes (81, 211, 324, 375, 435). A wealth of
additional evidence suggests that the Rap1/Gcr1 assemblage
MICROBIOL. MOL. BIOL. REV.
participates directly in an activation mechanism shared by this
common set of target genes. First, Gcr1 activation of glycolytic
and RP genes is eliminated by point mutations or small dele-
tions that eliminate the Rap1 binding site(s) in the correspond-
ing promoters (374, 375). Thus, the capacity of Gcr1 to stim-
ulate transcription of most if not all of its target genes is
entirely dependent upon Rap1 binding upstream of those
genes. Second, mutational inactivation of leucine zipper-me-
diated Gcr1 homodimerization eliminates both the GCR1 con-
tribution to activation of Rap1 target genes and complemen-
tation of the gcr1⌬ phenotype (81, 82). Indeed, loss of Gcr1
function and reduced transcriptional activation of Rap1 target
genes exhibit a tight correlation across an entire spectrum of
lesions that cause mild to severe impairment. Finally, fluores-
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cently tagged Rap1 and Gcr1 colocalize to foci in the yeast
nucleus in live cells (236), and epitope-tagged Rap1 and Gcr1
coimmunoprecipitate (375) and can be detected in a large
(⬎1-MDa) complex by size affinity chromatography; this Rap1
complex exhibits faster migration in the absence of Gcr1, in-
dicating that it is not an aggregation artifact (H. Zhou and
G. M. Santangelo, unpublished data).
Despite these data and other experimental support for the
hypothesis that Rap1 and Gcr1 collaborate directly to stimu-
late transcription of both glycolytic and RP genes, it has been
difficult to rule out a competing idea, that the effect of GCR1
deletion on RP gene expression is indirect. This alternative
hypothesis is based on the observation of coordinate regulation
of the 138 RP genes in S. cerevisiae. Coordinate regulation
links transcription of RP and other translational component
genes to the growth rate of yeast cells (93, 185, 409). The idea
that removal of Gcr1 indirectly causes a drop in RP transcrip-
tion involves the following reasoning: the reduction in glyco-
lytic gene transcription, which is a direct result of GCR1 dele-
tion, causes a severe defect (slow growth relative to wild-type
cells); this low growth rate in turn causes reduced RP gene
transcription via a Gcr1-independent mechanism of coordinate
regulation. According to this hypothesis, the rationale for as-
signing the “sick phenotype” label to the gcr1⌬ mutant is the
supposition that a bottleneck in energy generation takes place:
reduced glycolytic flux in glucose-grown gcr1⌬ cells impairs
anaerobic metabolism, while glucose repression of aerobic me-
tabolism remains intact. This unfortunate combination would
leave cells with no good way to generate energy, thereby ex-
plaining the slow growth and indirect reduction in RP tran-
scription.
Three independent lines of evidence demonstrate that this
alternative hypothesis is inviable. First, it is now clear that
glucose repression is not intact in gcr1⌬ cells (327, 383). Sec-
ond, analysis of strains that harbor partially functional GCR1
alleles identified several that grow and ferment glucose almost
as well as the wild type but nevertheless exhibit RP transcrip-
tion as defective as that observed in gcr1⌬ cells (81). Third, the
gcr1⌬ defect in RP transcription is equivalent in all ferment-
able carbon sources tested thus far (glucose, sucrose, raffinose,
and galactose), which, significantly (see above), includes non-
repressing sugars and pyruvate, a nonfermentable carbon
source (Fig. 5). Together these data eliminate the key under-
lying assumption of the alternative hypothesis, i.e., that in the
absence of Gcr1, glucose repression and/or slow growth causes
an indirect effect on RP expression.
VOL. 70, 2006
FIG. 5. Transcriptomic analysis of defective gene expression in
gcr1⌬ cells. Microarray hybridization was done with RNA from iso-
genic gcr1⌬ versus wild-type cultures grown to mid-logarithmic phase
(a density of 1 ⫻ 106 cells/ml) on each of the carbon sources indicated
(2% glucose, 3% sucrose, or 3% pyruvate). Total RNA was extracted
(408) and labeled with either Cy3-CTP or Cy5-CTP by using a low-
RNA-input fluorescent linear amplification kit (Agilent Technologies,
Palo Alto, CA). Labeled RNA was purified with the RNeasy MinElute
kit (QIAGEN) and hybridized to yeast 60-mer oligonucleotide arrays
(Agilent Technologies, Palo Alto, CA) according to the manufactur-
er’s recommendations. Array slides were scanned at 10-␮m resolution
with two-line averaging by using an Axon GenePix 4200A scanner and
GenePix 6.0 software. Hierarchical clustering was done with Acuity
4.0, with a centered Pearson similarity metric. The data shown here
represent an average of two replicate arrays, including a dye-swap
control. The scale shows color intensity proportional to the log ratio of
expression in gcr1⌬ cells (relative to the corresponding wild-type val-
ues). The cluster diagram shows the results for the 192 genes (11
glycolytic, 110 ribosomal protein, 4 translational component, and 67
other genes) that, in all three carbon sources, exhibit at least a twofold
decrease in expression in gcr1⌬ cells.
Therefore, especially when combined with new insights con-
cerning the shared participation of Rap1, Gcr1, and Gcr2 in
perinuclear gene regulation (see below), it is now apparent
that these global regulators work together to stimulate tran-
scription of both glycolytic and RP genes, the two largest and
most abundantly transcribed classes of glucose-induced target
genes in yeast cells. Much work remains in deciphering the
physical organization and relative contributions of the Rap1/
Fhl1/Ifh1 and Rap1/Gcr1/Gcr2 assemblages and how they are
signaled by the PKA and TOR pathways in response to the
appearance of glucose. Significantly in this regard, the conse-
quences of removing Gcr1 include a dramatic drop in transla-
tion rate, a decrease in CLN transcription, a cln3⌬-like in-
crease in cell size, and conditional cell cycle arrest and
elongated morphology in the cln3⌬ and cln1⌬ cln2⌬ back-
grounds (83, 416). An important topic for future investigation
GLUCOSE SIGNALING IN S. CEREVISIAE 269
is whether (and to what extent) the respective Sfp1/Fhl1/Ifh1
and Gcr1/Gcr2 contributions to Rap1 transcriptional activa-
tion and cell cycle control are coordinated.
The Repressor/Activator Theme in Glucose Regulation
Although some information has been gleaned regarding the
all-important events downstream of the transcriptional regula-
tory factors that mediate repression and derepression of glu-
cose-responsive target genes, a more than rudimentary under-
standing of the central mechanism(s) of gene regulation in S.
cerevisiae and other eukaryotes has thus far eluded our grasp.
Like Mig1, Mig3, Nrg1, and Rgt1, many of the factors that bind
DNA either directly or indirectly are capable of both activating
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and repressing transcription. This puzzling property of glucose
repressors is also true of positively acting regulators such as
Rap1 and Gcr1, as well as RNA polymerase II holoenzyme
components such as Med1, Ssn8, Sin4, and Rgr1 (15, 58, 210,
242, 346).
How a distinction is made between these diametrically op-
posite activities of activation and repression based on chromo-
somal and/or environmental context, as well as the molecular
mechanisms that execute this decision, awaits clarification. For
example, an unambiguous finding regarding the mechanism of
glucose repression in yeast cells is that the Ssn6/Tup1 core-
pressor complex plays an important role downstream of most
of the factors that bind DNA directly, such as the MIG-, NRG-,
and RGT1-encoded repressors. However, upon derepression
both Mig1 and Ssn6/Tup1 remain associated with glucose-
repressed promoters (29, 278, 279). Further, even Ssn6 appears
to be capable of stimulating transcription under some circum-
stances (68). Thus, most if not all of the relevant negatively
acting regulators remain associated with target promoters but
are somehow inactivated (or their activities are reversed) un-
der derepressing conditions. This is a much more subtle regu-
latory mechanism, and it operates on a much more static pro-
tein-DNA complex, than was previously believed to exist. The
final sections of this review will describe a new paradigm for
eukaryotic gene activation and regulation that may provide a
superior context in which to understand these and other inter-
esting new observations about glucose regulation in the yeast
nucleus.
Reverse Recruitment: Rap1/Gcr1 Activation
at the Nuclear Periphery
Beyond its interesting regulatory role in yeast cell physiol-
ogy, a second mystery has shrouded the Rap1/Gcr1 mechanism
of transcriptional activation: it conforms poorly with the re-
cruitment paradigm of gene regulation (36, 70, 295, 296, 352,
434). For example, when a Rap1 binding site is placed up-
stream from heterologous reporter genes, or when the activity
of Rap1-Gal4 or Rap1-LexA fusion proteins is measured,
Rap1 activation is surprisingly weak (in some contexts it is
undetectable) (38, 88, 349, 415). In contrast, mutational inac-
tivation of Rap1 binding sites in the very strong glycolytic
promoters typically results in a 10- to 20-fold decrease in tran-
scription, suggesting that Rap1 is a powerful activator (see,
e.g., reference 374). This discrepancy, with identical Rap1
binding elements yielding very different results depending on
270 SANTANGELO
whether they are in their native location or upstream from a
reporter, is paradoxical because no yeast protein other than
Rap1 binds to its recognition motif in DNA. Moreover, weak
Rap1 activation of reporter genes is not due to a structural
perturbation resulting from fusion to a heterologous DNA
binding domain; Rap1-LexA fusion proteins that can fully
complement a deletion of endogenous RAP1 show little or no
heterologous activity as transcriptional activators. This was
originally thought to indicate a requirement for additional
DNA-bound proteins (such as chromatin-remodeling factors)
for full activation by Rap1 and its coactivators, but to date no
arrangement of DNA motifs has been described that allows an
isolated Rap1 site to promote transcription as efficiently as its
native counterparts in glycolytic promoters.
An alternative explanation, which remains untested, is that
cooperativity resulting from coupling of the various steps in
transcription (i.e., activation, elongation, termination, process-
ing, and export of the final products to the cytoplasm [225])
explains the impressive strength of Rap1 activation when the
protein is bound at its native sites. Inclusion of mRNA export
in such a holistic mechanism of gene expression implies a
functional and/or physical connection with nuclear pores. This
“gene expression machine” (GEM) explanation for the dis-
crepancy in Rap1 activation efficiency is plausible because a
pas de deux between chromatin and GEMs, an arrangement
that could have evolved to optimize expression of naturally
occurring promoter-open reading frame combinations whose
products are in high demand, would be difficult to reproduce
with a heterologous gene. (A similar discrepancy has been
observed for transcriptional repression by Ssn6/Tup1, which is
much stronger in natural promoters than in artificial constructs
[194, 203]). Since most GEMs in glucose-grown cells appear
to be occupied with Rap1-regulated transcription units (see
above) (392, 416), this would explain why Rap1 activation (and
perhaps all glucose-regulated transcription) is unusually diffi-
cult to reproduce via the ubiquitous heterologous reporter
assay. An important corollary of this idea is that an accurate
working model for gene regulation will require detailed map-
ping of nuclear architecture (169, 200, 238–240, 280, 281).
Interestingly, the “gene gating” hypothesis proposed by
Günther Blobel in 1985 (22) may prove to have been a partic-
ularly perceptive early suggestion for how three-dimensional
structure in the nucleus is used to mediate (and regulate) gene
expression.
A second prominent aspect of the Rap1 activation mecha-
nism that conforms poorly with the recruitment model of gene
activation is the nature of the Gcr1 activation domain. This
domain is irreducibly large (280 residues) and can be subdi-
vided into at least four distinct hypomutable regions (82, 83);
two of these hypomutable regions coincide with predicted
transmembrane domains (236), and transmembrane-disrupt-
ing lesions in these domains are known to inactivate both
GCR1 function and Gcr1-LexA activation of a heterologous
reporter gene (82). If, as predicted by the recruitment model,
these transmembrane motifs are required for incorporation of
Gcr1 into its activation complex, it should have been possible
to make compensatory extragenic lesions that would suppress
at least one of the inactivating mutations. Exhaustive screens
for such suppressing lesions by using either irradiation or
MICROBIOL. MOL. BIOL. REV.
chemical mutagens have failed. Further, every mutation in this
region that inactivates GCR1 function also eliminates Gcr1-
LexA activation of a LexA-driven reporter gene. Since Gcr1-
dependent transcriptional activation of target genes is elimi-
nated by removal of the Rap1 binding site in the corresponding
promoters, this was originally interpreted to mean that contact
between Rap1 and Gcr1 is a requirement for the latter to
recruit the transcriptional machinery. However, targeted mu-
tagenesis of RAP1 has been equally unsuccessful in generating
detectable suppression of lesions in Gcr1 that impair activa-
tion. Furthermore, activation of a heterologous reporter by
Gcr1 persists long after the disappearance of Rap1 in RAP1ts
strains. Together these data suggest that when Gcr1 is bound
upstream from a reporter gene, its Rap1 interaction domain is
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required but (paradoxically) Rap1 itself is not. The large body
of existing data regarding the Gcr2 contribution to the Rap1/
Gcr1 activation mechanism has likewise been difficult to rec-
oncile with the recruitment paradigm (81, 435). Thus, all at-
tempts to resist the straightforward interpretation of an
activation domain that overlaps with transmembrane domains,
i.e., that Gcr1 association with the nuclear membrane is an
important feature of its transcriptional activation function,
have failed.
A recent genome-wide genetic screen (synthetic genetic ar-
ray analysis; see above) of gcr1⌬ and gcr2⌬ query strains
yielded a surprising result that has finally provided an im-
proved context for resolving these disparities and elucidating
the mechanism of Rap1/Gcr1 transcriptional activation. Both
GCR1 and GCR2 were found to be members of a large genetic
network of nucleoporin genes (236). More specifically, dele-
tion of each nonessential gene encoding a component of the
Nup84 subcomplex exhibits a synthetic genetic defect in com-
bination with GCR1 deletion. Follow-up biochemical, cell bi-
ological, and gene expression analyses confirmed that Rap1/
Gcr1 activation occurs at the nuclear periphery and is impaired
by disruption of genes encoding components of the Nup84
subcomplex. For example, Rap1 and Gcr1 are 100% and 71%
as enriched in nuclear envelope fractions as the integral nu-
clear membrane protein Pom152, unlike control proteins such
as the nucleolar factor Nop1 (⬍1% enriched) (236). Impor-
tantly, perinuclear localization of Rap1/Gcr1 target genes has
been observed via chromatin immunoprecipitation of nuclear
pore-associated genes (48), which provides independent sup-
port for the conclusion that there is a physical and functional
link between the Rap1/Gcr1 assemblage and the nuclear rim.
Most surprisingly, not only do Rap1 and its coactivators
Gcr1 and Gcr2 activate transcription at the nuclear periphery,
but many yeast nucleoporins function as transcriptional acti-
vators; two of these were shown to do so at their normal
perinuclear location (236). Transcriptional activation by nu-
cleoporins is severely impaired by GCR1 deletion, suggest-
ing that disruption of the Rap1 activation assemblage inter-
feres with the normal organization of GEMs at the yeast
nuclear periphery. This result may recapitulate a phenomenon
relevant to human cancer. Perinuclear gene activation appears
to be oncogenic in acute myeloid leukemia and related syn-
dromes in humans, in which chromosomal rearrangements
fuse Hox DNA binding domains to the nucleoporin hNup98
VOL. 70, 2006
FIG. 6. Both Gcr1 and Rpo21 are related to the RNA polymerase II large-subunit gene from M. invertens. The N terminus and carboxy-terminal
domain (CTD) of Rpo21 exhibit strong homology with their M. invertens counterparts, whereas the internal region of the M. invertens protein
exhibits weaker (although highly significant) homology with both Rpo21 and Gcr1. The transmembrane domains of Gcr1 (TM1 and TM2), as well
as its primary homodimerization domain (1LZ), all of which make a critical contribution to Gcr1 function (see the text), exhibit ⬎80% similarity
with the M. invertens RNA polymerase large subunit, as indicated.
(126, 183). Interestingly, human Nup98 also activates tran-
scription in yeast cells, and its ability to do so is impaired in the
absence of Gcr1 (236). Integral GEM components, including
several Mediator subunits (Ssn8, Sin4, and Med1) and Rpo21,
also associate with the nuclear periphery and participate in
perinuclear activation.
These data indicate the existence of an unusually intimate
relationship between the Rap1/Gcr1 assemblage and GEM
components, a conclusion that is further suggested by protein
sequence similarity searches. For example, PSI-BLAST analy-
sis of Gcr1 identified homology with the RNA polymerase II
large subunit in the free-living protist Mastigamoeba invertens
(Fig. 6) (351). The highly significant E value of this pairing is
2.0 ⫻ 10⫺30 (marginal significance is attained at an E value of
0.05 [5]). M. invertens and other primitively amitochondriate
members of the order Pelobiontida may represent the earliest
eukaryotic lineages (351). Thus, the RNA polymerase II large-
subunit gene in M. invertens could represent a composite pre-
cursor of both Rpo21 and Gcr1 (Fig. 6). This potential primor-
dial connection between nuclear pores and Rap1/Gcr1/Gcr2
function may help to explain the lack of evolutionary conser-
vation of the latter; divergence of the nucleoporin Nup96 has
been shown to cause hybrid inviability in Drosophila and may
therefore contribute to speciation (293).
These new data begin to place the Rap1/Gcr1 activation
assemblage within its proper architectural context in the yeast
nucleus and (at least where this unusual regulatory complex is
concerned) suggest an interesting alternative to the recruit-
ment model of transcriptional activation. We have termed this
alternative paradigm “reverse recruitment” to highlight its cen-
tral feature, that Rap1/Gcr1 target genes are recruited to pe-
rinuclear GEMs; the term references the opposite presump-
tion of the recruitment model, that the requisite factors are
drawn to (or assembled on) the relevant promoters. Impor-
tantly, although this mechanism was uncovered through the
GLUCOSE SIGNALING IN S. CEREVISIAE 271
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discovery of a functional connection between the Rap1/Gcr1/
Gcr2 activation assemblage and GEMs at the nuclear rim, the
reverse recruitment model does not imply that all activation
occurs at the nuclear periphery. Indeed, promyelocytic leuke-
mia protein bodies in the nuclear lumina of mammalian cells
(61, 290, 399) could represent nodes of GEM organization that
parallel what we have observed to occur at nuclear pores in
yeast cells. In this regard, the reverse recruitment idea is con-
sistent with an earlier proposal by Hutchison and Weintraub
that active eukaryotic genes are localized along interchromatin
channels that communicate with the nuclear periphery (167).
Thus, the central feature of the reverse recruitment idea is that
genes become transcriptionally active by docking with com-
partmentalized GEMs. Although they are relatively abundant
at the periphery, it seems likely that at least some GEMs are
luminal; these internal GEMs may nevertheless maintain func-
tional and/or physical communication with their perinuclear
counterparts.
The reverse recruitment idea explains much or all of the
data that seemed paradoxical when attempting to fit them
within the recruitment model. It presumes that Rap1 and Gcr1
are separate cogs in a large and multifaceted GEM and that
the site of Gcr1 attachment to this megalith is an extensive
hydrophobic interaction with either the Nup84 subcomplex, an
adjacent site on the nuclear envelope itself, or both (Fig. 7).
Thus, there may be two types of reverse recruitment in S.
cerevisiae, i.e., transient occupation of GEMs by tightly regu-
lated (and often weakly expressed) genes and constitutive oc-
cupation by strongly expressed genes that bind directly to a
GEM component; the Rap1/Gcr1 mechanism is in the latter
category. According to this idea, regulation of Rap1/Gcr1 tar-
get genes, which clearly does occur (e.g., upshift upon the
appearance of glucose), might involve a novel type of regula-
tory control: alteration of the functional or physical relation-
ship between perinuclear GEMs and the Rap1/Gcr1 assem-
blage.
272 SANTANGELO MICROBIOL. MOL. BIOL. REV.

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FIG. 7. Perinuclear transcriptional activation of Rap1/Gcr1 target genes via reverse recruitment. Known components of the Rap1 activation
(Gcr1/Gcr2) or silencing (Sir complex) assemblages are shown. Essential nucleoporins are indicated with an asterisk. Dashed lines highlight
presumptive perinuclear tethering interactions; nuclear pore complex-associated factors shown to interact with Gcr1 are underlined. The
representation shown here is not intended to rule out the existence of a unified complex that can switch between activation and repression of
transcription. (Reprinted from reference 236 with permission of the publisher. Copyright 2005 National Academy of Sciences, U.S.A.)

GENE REGULATION VIA REVERSE RECRUITMENT Rap1 repression of target genes upon disruption of the secre-
tory pathway (208) and Rgt1 activation of HXT1 (see above).
A New Model for Eukaryotic Transcriptional Activation
Ghost regulation cannot be reconciled with a competitor of the
and Repression
reverse recruitment idea that postulates an alternative expla-
As described above, the existing data suggest that reverse nation for the perinuclear location of activated GAL and INO
recruitment accounts for the bulk of transcriptional activation genes, i.e., that transcription initiation complexes form as pre-
in growing yeast cells. What about more conventional regula-
tory systems: does reverse recruitment explain all types of
transcriptional activation and regulation in eukaryotic nuclei?
Data favoring this conclusion are already available for two
conventional regulatory mechanisms, INO and GAL (32, 48)
(Fig. 8). With respect to the well-studied GAL system, tran-
scriptional activation in galactose-grown cells is accompanied
by association between GAL genes and the nuclear periphery,
which is dramatically reduced in glucose-grown cells (48). This
result is particularly significant because analyses of galactose-
regulated gene expression and the Gal4 activator were used
initially to establish the recruitment paradigm. The link be-
tween transcriptional activation and perinuclear association
has also been reported for INO1 (32). Thus, a growing body of
evidence supports the ideas that a link exists between the
nuclear periphery and transcriptional activation and that re-
versible association with the nuclear rim may be an integral
feature of all eukaryotic gene regulation (see also a recent
analysis of var genes in Plasmodium falciparum [301]).
FIG. 8. Perinuclear transcriptional activation of GAL genes via re-
Universal application of the reverse recruitment paradigm verse recruitment. The glucose-regulated transcriptional activator
may provide a context in which to understand numerous per- Gal4 associates with its DNA binding sites whether the downstream
plexing phenomena that have heretofore defied explanation, target genes are inactive or active, as shown. The GAL1, GAL7, and
most importantly the capacity of regulators to exert influence GAL10 genes are not detectably associated with the nuclear periphery
under conditions (in glucose-grown cells) in which their transcription is
on gene transcription under circumstances where either direct repressed (UNINDUCED, left side). When cells are grown in the
or indirect contact with the DNA is thought to be unlikely. The presence of galactose, these same GAL genes associate with the nu-
best-characterized examples of such “ghost regulation” are clear periphery (INDUCED, right side).
VOL. 70, 2006 GLUCOSE SIGNALING IN S. CEREVISIAE 273

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FIG. 9. A model for glucose regulation at the nuclear periphery of S. cerevisiae. Numerous regulators involved in the transcriptomic response
to glucose are components of a large nuclear assemblage (gene expression machine) that is tethered to nuclear pores (dashed lines) via multiple
interactions with the Nup84 subcomplex. Red arrows depict repressed target genes, and green arrows depict activated targets. Inactivation of
DNA-bound regulators (Mig1, Mig3, and Nrg1) by the Snf1 kinase is predicted to involve a subtle conformational alteration that remains obscure.
Many of these glucose regulatory factors, including components of the RNA polymerase II Mediator, are bifunctional factors that can either
repress or activate transcription in a context-dependent fashion (shown here for Rap1). This facile switching between transcriptional readouts
underscores the mechanistic subtlety of regulatory partnering and/or conformational specificity. Association between nuclear pores and the
Gcr1/Gcr2 complex is required for transcriptional activation by both Rap1 and Nup84 subcomplex components (229). The perinuclear Rap1/
Gcr1/Gcr2 assemblage thus allows productive access to GEMs by glucose-induced (glycolytic and RP) genes tethered at the nuclear periphery.

dicted by the recruitment model and move to the periphery
only during the final stages of gene expression (i.e., during
mRNA processing and export).
Glucose May Signal a Highly Networked and Structurally
Stable Perinuclear Machine
Another recent development favoring the reverse recruit-
ment idea is that proteins capable of both induction and re-
pression of transcription, including many involved in glucose
regulation (e.g., Rap1, Gcr1, Snf1, Mig1, Mig3, Nrg1, Rgt1,
Ssn6, Med1, Ssn8, Sin4, Rgr1, and Fhl1), appear to be the rule
rather than the exception. We have now shown that many of
these factors are concentrated at the periphery of the yeast
nucleus (236; B. B. Menon and G. M. Santangelo, unpublished
data). It is increasingly clear that subtle allosteric alteration of
bifunctional activator/repressor-type regulators is a common
mechanism responsible for major regulatory shifts in the tran-
scriptome (e.g., at Snf1/Mig1/Ssn6 targets). Reverse recruit-
ment has the advantage of allowing a straightforward and par-
simonious depiction of this type of subtle gene regulation
mechanism (Fig. 9), a task that has become more and more
difficult and convoluted when one adheres to the recruitment
paradigm. This is in part because the latter requires so many
factors to assemble in the correct configuration at each pro-
moter. It is especially so when also considering that the re-
cruitment model requires them to assemble in the proper
sequence (i.e., in a temporally flawless fashion) at each pro-
moter, or to preassemble and then bind as a complex or series
of complexes, in order to obtain the proper transcriptional
readout for each corresponding gene. Indeed, a recent ge-
nome-wide analysis of quiescence revealed that, in contrast
with the recruitment model, RNA polymerase II is already
positioned upstream of many inactive genes prior to their in-
duction upon exit from stationary phase (298).
With respect to glucose regulation in particular, it is also
now apparent that DNA-bound transcriptional activators,
readily identified in some systems (e.g., Gal4), may be curi-
ously missing from others. Given that SUC2 has been a model
target gene in the study of glucose repression, it is reasonable
to have expected by now the identification of a DNA-bound
SUC2 activator. (Although it seems unlikely, it remains a for-
mal possible that the gene encoding the SUC2 activator protein
has simply eluded detection.) The very successful screens for
non-sucrose-fermenting mutants (46, 259, 385) have instead
identified the critically important kinase subunits Snf1 and
Snf4, a putative glucose sensor localized to the plasma mem-
brane (Snf3), endosomal factors (Snf7 and Snf8 [148, 287]),
and components of the Swi/Snf chromatin remodeling complex
(Snf2, Snf5, Snf6, Snf11, and Snf12). None of these proteins
are thought to bind DNA directly. Subsequent screens for
suppressors of Snf1 (47, 386) identified two critical down-
274 SANTANGELO
stream factors in glucose repression, Mig1 (Ssn1) and Ssn6; the
products of the other six SSN alleles associate biochemically
with RNA polymerase II and participate in the Mediator-
based mechanism of glucose repression by the Ssn6/Tup1 core-
pressor: Ssn2, Ssn3, Sin4 (Ssn4), Srb8 (Ssn5), Rox3 (Ssn7),
and Ssn8.
Thus, of all these Snf and Ssn loci, the only protein identified
to date that exhibits specific DNA binding activity is the zinc
finger protein Mig1. Mig1 (and its paralogs Mig2 and Mig3)
bind to a GC core element upstream from SUC2 and other
glucose-regulated genes. Mig1 and Mig3, like most of the other
transcription factors identified in Snf and Ssn screens, are
known to function as both repressors and activators. Never-
theless, Mig1 is presumed not to participate in activation of
SUC2, which it binds to and represses in the presence of glu-
cose. This conclusion is based on three assumptions that are
well worth revisiting. First, SUC2 is derepressed normally in
the absence of MIG1 (and/or MIG2). However, the redun-
dancy of factors that bind to similar GC recognition sites in
DNA makes it difficult to construct a strain in which all regu-
lators that could bind and activate transcription are known to
be eliminated. Thus, it is quite possible that MIG deletion
uncovers a cryptic activator function in the SUC2 promoter.
Second, Mig1 relocates to the cytoplasm in the absence of
glucose. However, the Mig1 molecules remaining in the nu-
cleus are sufficient to occupy binding sites upstream of Mig1
target genes (see above). Third, removal of the Mig1 recogni-
tion motif in the promoter does not impair SUC2 derepression.
However, this argument rests on the assumption that the re-
cruitment model of transcriptional activation is correct, and
that once binding of those factors to their respective DNA
recognition sites is blocked, they no longer remain in the vi-
cinity of (i.e., tethered to) their respective target genes. In
contrast, the reverse recruitment hypothesis postulates that a
given regulator may remain in the vicinity of a “tethered”
target gene and continue to influence its expression by altering
the behavior of associated GEMs. This leaves open the possi-
bility that Mig1 and other factors originally identified as re-
pressors (e.g., Rgt1) might, in contrast to previous expecta-
tions, undergo a repressor-to-activator switch and activate
their target genes under derepressing conditions (Fig. 9).
Reverse recruitment thus provides a viable alternative to an
increasingly untenable prediction of the diffusion-based re-
cruitment model that a disparate collection of activators, re-
pressors, coactivators, corepressors, and GEM components are
brought to each promoter as needed to provide the appropri-
ate regulatory input. An improved understanding of nuclear
substructure and its reception of regulatory signals from the
plasma membrane and cytoplasm is therefore a critical prereq-
uisite to constructing an accurate global wiring diagram for
glucose signaling in S. cerevisiae and other eukaryotes. Reas-
sessment of the regulatory relationships in other systems will
likewise become necessary if reverse recruitment is as wide-
spread an explanation for gene induction and repression as
now seems plausible.
ACKNOWLEDGMENTS
I am extremely grateful to Kristine Willis for figure design and
preparation, to Youping Deng and Venkata Thodima for the graphical
depiction of the ClustalW alignment of Gcr1 and Rpo21 with their M.
MICROBIOL. MOL. BIOL. REV.
invertens homolog, to Kellie Barbara for graciously contributing the
microarray data shown in Fig. 5, to Kellie Barbara and Nicole Thomp-
son for help with literature searches, and to Kristine Willis, Jeong-Ho
Kim, Kelly Tatchell, Lucy Robinson, and Brenda Andrews for review-
ing the manuscript, as well as for their keen insight and tolerance. Most
importantly I thank the current and past members of the Santangelo
laboratory for their perspiration, inspiration, and helpful suggestions.
Finally, kudos and thanks to the many fine biomedical researchers in
Mississippi with whom I have collaborated during my tenure as Direc-
tor of the Mississippi Functional Genomics Network (mfgn.usm.edu
/mfgn).
Work in my laboratory is supported by National Institutes of Health
award RR16476.
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