Concept of Cell Signaling

(trans-membrane signal)
Signal Transduction and
Related Diseases The process in which cells sense the extracellular
stimuli through membranous or intracellular
receptors, transduce the signals via intracellular
刘永明 molecules, and thus regulate the biological function
LIU Yongming of the cells

Department of Pathophysiology,
Wuhan University

Signal transduction
In biology, signal transduction refers to any process
by which a cell converts one kind of signal or
stimulus into another.
Most processes of signal transduction involve
ordered sequences of biochemical reactions inside
the cell, which are carried out by enzymes,
activated by second messengers, resulting in a
signal transduction pathway and biological effect. General process for
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transmembrane signal transduction

Cellular Signal
transduction
Figure 15-1 Molecular Biology of the Cell (© Garland Science 2008) 5

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 Nobel Prizes for signaling transduction Signal
Year Recipient Area of Research

genetic regulation of organ development and

Cells respond to their environment by
reorganizing their structure, regulating the activity
2002 S. Brenner, H. R. Horvitz, J. E. Sulston
programmed cell death (PCD).

2001 L. H. Hartwell, R. T. Hunt, P. M. Nurse key regulators of the cell cycle of proteins and altering patterns of gene
2000 A. Carlsson, P. Greengard, E. Kandel Signal transduction in the nervous system expression.
1999 G. Blobel Signal hypothesis of protein translocation

1998 R. Furchgott, L. Ignarro, F. Murad Role of NO as cellular messenger

The stimulus for such responses is termed a
1994 A. Gilman, M. Rodbell Structure and function of GTP-binding(G) proteins signal, and may be a small molecule, a
1992
E. Fischer, E. Krebs Alteration of enzyme activity by phosphorylation macromolecule or a physical or chemical agent…
/dephosphorylation

1971 E.W. Sutherland Mechanism of hormone action and cyclic AMP

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Types of cellular signals

Signaling Molecules
(1) Physical signals Inculde proteins, small peptides, amino acids,
Light, electronic, mechanic, UV, heat,
volume or osmotic, etc nucleotides, fatty acid derivatives, and even
dissolved gases such as nitric oxide (NO) and
(2) Chemical signals
Hormones, neurotransmitters,, cytokines; carbon monoxide (CO) etc.
odor molecules; active oxygen; drugs, toxins,
etc

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Extracellular Signaling Molecules

Chemokines are a family of small cytokines, or
Hormones are chemicals released by cells that
proteins secreted by cells
affect cells in other parts of the body.
(involved in pro-inflammatory response or
(Endocrine hormone molecules VS controlling the migration of cells during normal
paracrine/autocrine hormone molecules) processes of tissue maintenance or development)

Neurotransmitters are chemicals that are used to

relay, amplify and modulate signals between a
neuron and another cell.

13 14

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 Extracellular signals can act slowly or rapidly to change
Four forms of intercellular signaling
the behavior of a target cell
autocrine

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Figure 15-4 Molecular Biology of the Cell (© Garland Science 2008) Figure 15-6 Molecular Biology of the Cell (© Garland Science 2008)

Intracellular signaling molecules Receptors

The small molecular material that transmits messages in
cells
The secondary messengers include calcium ion（Ca2+ ）,
diacylglycerol（DAG）, inositol triphosphate（IP3）, cyclic
adenosine monophosphate（cAMP）, cyclic guanosine
monophosphate（ cGMP）, arachidonic acid and its
metabolite etc（et cetera） .
The third messenger is the material responsible for
information transmission inside and outside cell nucleus, is
also called the DNA binding protein.
Receptors are proteins or glycolipids located in the plasma
membrane or inside the target cells, which can specifically
recognize biological active molecules (signal molecules)
and transmit signals into the cell .
The biological active molecules that can recognize and
bind to receptors are called ligands.

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Major pathways for cell signaling

Transmembrane receptors
G-protein-mediated pathway
Adenylate cyclase mediated pathway
Phospholipase mediated pathway
Small G-protein-mediated pathway

Non-G-protein-mediated pathway
Receptor tyrosine kinase (RTK) mediated pathway
Receptor serine/threonine kinase mediated pathway
Receptor guanilate cyclase mediated pathway
Intracellular (nuclear) receptor mediated pathway

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 I. G-protein-coupled receptors (GPCRs)
activate an intracellular G-protein that in turn activates
intracellular enzymes
“for their transduction in cells discoveries of G-proteins
and the role of these proteins in signal”
The G-protein-coupled receptors (GPCRs)
Signaling through G-protein-coupled-receptors
Ø The most important pathway of transmembrane
signal transduction
Ø The largest family of cell-surface receptors, more
than 700 GPCRs in humans,
Ø The same signal molecules can activate many
different GPCR family members,
Ø About half of all known drugs work through GPCRs
or GPCR-mediated signaling pathways
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 G-protein-Mediated Pathway Activation of Adenylate Cyclase by Gsα

GTPase

Activation cycle of a G-protein (purple) by a G-protein-

Regulation of G-Protein Activity coupled receptor (light blue) receiving a ligand (red) 31

GPCR mediated-
cAMP signaling

PKA: cAMP-dependent protein kinase;

CRE: cAMP-response element;
Activation of a G protein by CREB: CRE-binding protein;
an activated GPCR Figure CBP: CREB-binding protein
Figure 15-32 Molecular Biology of the Cell (© Garland Science 2008) 32 15-36 Molecular Biology of the Cell (© Garland Science 2008)
33

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 GPCR increase cytosolic Ca2+ and activate PKC

Effectors

PKC: a ser/thr protein kinase, Ca2+-dependent

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Figure 15-39 Molecular Biology of the Cell (© Garland Science 2008) Table 15-1 Molecular Biology of the Cell (© Garland Science 2008)

1. AC/PKA pathway：
(Adenylate cyclase / protein kinase A)

G-protein signal transduction:

Gαs (Gαi)：AC/PKA pathway

Gαq：PLCβ → PIP2 →
IP3/ Ca2＋ pathway
DAG/PKC pathway

2. IP3/ Ca2＋ pathway：

(1’4’5-inositol triphosphate)

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 3. DAG/PKC pathway：
(1’2-diacylglycerol, [daɪæsɪl'glɪsərɒl]

Small GTP-binding proteins II. Enzyme-coupled receptors

w Ras (growth factor signal cascades).
w Rho (regulation of actin cytoskeleton)
w Rab (vesicle targeting and fusion).
The receptors either has “the enzyme” activity (kinase) or
associate with enzymes (kinases) that they activate.
The protein kinases can phosphorylate specific sets of
proteins in the target cells when activated.

w ARF (forming vesicle coatomer coats).

w Ran (transport of proteins into & out of the
nucleus).
All GTP-binding proteins differ in conformation
depending on whether GDP or GTP is present at their
nucleotide binding site.
Generally, GTP binding induces the active state. homodimer heterodimer
Figure 15-16c Molecular Biology of the Cell (© Garland Science 2008) 43

Some subfamilies of RTKs

Signaling through enzyme-coupled receptors

Ø Receptor tyrosine kinases

(RTKs/RTPKs):
Ras,
PI3K,
PLCγ

Ø Non RTPK pathway:

JAK, STAT

44 Figure 15-52 Molecular Biology of the Cell (© Garland Science 2008)

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 The binding of SH2/SH3 containing intracellular signaling proteins
to an activated PDGF receptor

Table 15-4 Molecular Biology of the Cell (© Garland Science 2008) 46

RTK activates Ras, a monomeric GTPase

Figure 15-58 Molecular Biology of the Cell (© Garland Science 2008) 48

MAPK signal transduction:

Stress, GPCR, Stress,
Growth factors, Inflammatory cytokines, Growth factors,
Stimulus Mitogen, GPCR Growth factors Mitogen, GPCR

Raf, Mos, MLK3, TAK, MEKK1, 4, MEKK2, 3,

MAPKKK Tpl2 DLK MLK3, ASK1 Tpl2

MAPKK MEK1/2 MKK3/6 MKK4/7 MEK5

MAPK ERK1/2 p38 MAPK JNK1,2,3 ERK5/BMK1

Growth, Inflammation, Growth,

Biological Differentiation, Apoptosis, Growth, Differentiation,
responses Development Differentiation Development

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 PI3K signal pathway

III. Ion-channel-coupled receptors Intracellular receptors

They are involved in rapid synaptic signaling between nerve cells and
other electrically excitable target cells such as nerve and muscle cells
Some receptors are located in the cytoplasm , and
transformation allows nuclear translocation ;
Others are already present in the nucleus, functioning as
transcription factors
eg. The steroid hormone receptor superfamily:
receptors for steroid and thyroid hormones, and vitamins
A and D and their derivatives
NFκB
STAT

56 57

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 The nuclear receptor superfamily

Figure 15-3 Molecular Biology of the Cell (© Garland Science 2008) 58 Figure 15-14a Molecular Biology of the Cell (© Garland Science 2008) 59

The nuclear receptor

60 NF-κB Signaling Pathway

Signal-transducing pathways summary

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Figure 15-17 Molecular Biology of the Cell (© Garland Science 2008)

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Features of signal-transducing systems
Specificity
Signal molecule fits binding site on its complementary
receptor; other signals do not fit. Signal transductions are
remarkably specific and exquisitely sensitive.
Amplification
When enzymes activate enzymes, the number of affected
molecules increases geometrically in an enzyme cascade.
Such cascades can produce amplifications of several orders
of magnitude within milliseconds.
Desensitization/Adaptation
Receptor activation triggers a feedback circuit that shuts off
the receptor or removes it from the cell surface. When a
signal is present continuously, desensitization of the
receptor system occurs; when the stimulus falls below a
certain threshold, the system again becomes sensitive.
Integration
A final noteworthy feature of signal-transducing systems is
integration the ability of the system to receive multiple
signals and produce a unified response appropriate to the
needs of the cell or organism.

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Divergence
the stimulus of a receptor activates two parallel pathways

Cross-talk
one pathway branches off and interacts with another. All the
major signaling pathways in the cell use protein kinases
and phosphatases. There is a high level of interaction
between them.

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Aberrant Signal (Signal Excess) Aberrant Signal (Signal Insufficiency)

ischemia, epilepsy, neurodegenerative diseases
extracellular glutamate/aspartic acid Lesions in pancreatic β-cell
NMDAR activation
Decreased insulin production
Ca2+ influx
[Ca2+]i , activation of enzymes hyperglycemia
Ca2+ overload
Diabetes (Type I)

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 Aberrant Signal (autoimmune-thyropathy)

Stimulatory Ab
TSH-R Blocking Ab 2. Aberrant Receptor in Cell
30~35aa
residues
Signaling
Gs Gq TSH-R
295~302
AC PLC 385~395
AA residues • Receptor gene mutation
cAMP IP3 DG
Binding of TSH to R↓ • Receptor down regulation or
Ca2+ PKC desensitization
Thyroid proliferation & secretion #
hypothyroidism
hyperthyroidism

Receptor Gene Mutation Response of the insulin receptor kinase (IRK)

— Genetic insulin-resistant diabetes to ligand binding
IR gene mutations Heterotetramer (2α, 2β)
Insulin+R Insulin binding leads to
Activate RPTK Disturbances in synthesis change in structure
in transfer to the membrane Conformation change
IRS
in affinity to insulin activates β-subunit TK
activity
PI3K Ras/Raf/ in RPTK activation
β-subunit phosphorylates
MEK/ERK in proteolysis Tyr residues on
Glycogen cytoplasmic domains as
well as downstream
Synthesis, Cell substrates (IRS)
Transport proliferation
& Utilization Type II Diabetes

Once Tyr-Phosphorylated, the IRK activity Receptor Tyrosine Kinases

trigerrs a number of signaling pathways

Phosphatidylinositol 3-
hydroxy kinase, makes
PIP2,PIP3

Grb2, Sos, activates Ras

Activation of PLC

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 Receptor Gene Mutation
(Nephrogenic Diabetes Insipidus，肾性尿崩症)
ADH + ADHV2-R Gene mutation
Gsα V2R synthase↓
cAMP or affinity↓

ADH reaction in
AQP2 moves to lumen side in collecting tubules↓
collecting tubules
Diuresis(多尿)
Permeability↑
Nephrogenic Diabetes
H2O absorption #
Insipidus

Secondary Abnormality in Receptors

(Heart failure)

Myocardial hypertrophy
β-R1 down regulated or desensitized 3. Aberrant G-protein
Reaction to catecholamine in Cell Signaling
Myocardial contraction
Alleviate Accelerate
myocardial lesion heart failure

G-protein gene mutation—pituitary tumor

Gsα gene mutation

GHRH
GTPase activity
Pituitary
Persistent activation of Gsα
Gsα Persistent activation of AC
GH cAMP

Pituitary proliferation and secretion

Robert Wadlow, the tallest man known to have Gigantism
lived (2.72 metres or 8 feet 11 inches) with his

Acromegaly or Gigantism father (1.82 metres or 6 feet ) 巨人症

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 G-protein gene mutation—type 1A-PHP
PHP（Pseudohypoparathyroidism，
假性甲状旁腺功能低下） is a genetic disease caused
by Gsα gene mutation

type 1A ： Gsα gene mutation → expression of Gsα

→ disconnection between PTH receptor and AC →
hyperphosphatemia （高磷酸盐血症）

type 1B the target organ resists to PTH，

Normal Acromegaly the Gsα is normal
正常 肢端肥大症

Aberrant intracellular Signaling

Pro-carcinogen of phorbolester

PKC persistent activation

4. Aberrant Intracellular
Signaling Growth factors Na+/H+ exchange #
Cancer gene expression
Intracellular pH↑/ K+↑

Cell proliferation
(Cancer)

Aberrant intracellular Signaling

The intracellular signaling involves various

messengers, transducers and transcription factors. 5. Multiple Abnormalities in
Disorders can occur in any of these settings. Signaling Pathway
Calcium overload is a general pathological process
in various diseases; The level of NO is positively
correlated with ischemic injury; Stimulation of NF-κB
is seen in various inflammatory responses

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 cAMP
The sympathetic regulation in heart failure

Normal Hypertrophy, heart failure Ca2+channel SR phospholamban

Ca2+ influx Ca2+ pump SR pump↓
CA Density of SN↓；tyrosine hydroxylase↓
SR [Ca2+] i↓
β 1R β-R down regulated； Ca2+channel
pH↓→ reaction of R to CA↓ Myocardial dilation
[Ca2+] i
Gαs Gαs↓，function↓；Gαi #， function #
Myocardial contraction
cAMP H+ inhibits binding of
Ca2+ to troponin

Multifactor Aberrancies and Cancer

(Deficits in proliferation-inhibiting signal)
Multifactor Aberrancies and Cancer TGF-β + TGF-βR
(Enhancement of proliferating signals) PSTK activation Gene mutation

Ligands (GFs) Smad-phosphorylation

Negative regulation
Receptors (overexpression, activation of TPK) P21/P27/P15 expression
Intracellular transducers： Cdk4 inhibition Lymphoma,
Ras mutation Ras-GTPase Ras activation
Cell cycle arrests at G1 phase liver cancer,
Raf MEK ERK Proliferation TUMOR Stomach cancer
Inhibits cell proliferation
(pro-apoptosis)

7. Different receptors use same pathways

GPCR, RTKR, Cytokines Rs

6. Same Stimulant Induces
Different Responses
PLC Ras PI-3K
(the same stimuli can act on PKC Raf PKB
different receptors)
MEK

ERK

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 Cross talk—how hypertension
leads to myocardial hypertrophy?
Mechanic stimuli NE, AT-II GF TGF-β

Na+, Ca2+ influx PLC TPK PSTK

Na+-H+ exchange
Ca2+/PKC 9. Principles for Treatment of Aberrant
Ras Smad-P
Alkalization Signaling-related Diseases
Raf

MAPK
Transcription factors

Myocardial Hypertrophy

Principles for Treatment

• To regulate the level of extracellular molecules

• To regulate the structure and the function of
receptors
10. Application of Signal Transduction in
Scientific Research
• To regulate the level and modifications of
intracellular messenger molecules and transducers
• To regulate the level of nuclear transcription
factors

Regulating Signal Transduction in Research

Dominant negative effect? GF-109203X

P P P
PKC
AD
ADp- tau P
p- tau
PP Normal tau
Mutation causes not only self-dysfunction P P
P P
but also inactivates or inhibits wild type counterparts P
Caspase-3
P
P
The mutation is called dominant negative mutant S9/21
S9/21
T308 S473

Inactive
Active
Active P Inactive
For example, mutated nuclear receptor competes with GSK-3α/β
GSK-3α/β PKBα
wild type receptors to bind to the target gene WT
and thus inhibits the transcription activity of wild type P

genes PDK1/PDK2 PI3-K

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 Summary

Receptor
G-protein signal pathway
Enzyme-linked receptors (RTKs)
cytoplasmic and nuclear receptor
Signal transduction pathway disorder
（example）

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