Cell Tissue Res (2010) 339:237–246
DOI 10.1007/s00441-009-0821-y
REVIEW
Proteoglycans: from structural compounds
to signaling molecules
Liliana Schaefer & Roland M. Schaefer
Received: 31 March 2009 / Accepted: 8 May 2009 / Published online: 10 June 2009
# Springer-Verlag 2009
Abstract Our knowledge of proteoglycan biology has
significantly expanded over the past decade with the
discovery of a host of new members of this multifunctional
family leading to their present classification into three
major categories: (1) small leucine-rich proteoglycans, 2)
modular proteoglycans, and 3) cell-surface proteoglycans.
In addition to being structural proteins, proteoglycans play
a major role in signal transduction with regulatory functions
in various cellular processes. Being mostly extracellular,
they are upstream of many signaling cascades and are
capable of affecting intracellular phosphorylation events
and modulating distinct pathways, including those driven
by bone morphogenetic protein/transforming growth factor
superfamily members, receptor tyrosine kinases, the
insulin-like growth factor-I receptor, and Toll-like recep-
tors. Mechanistic insights into the molecular and cellular
functions of proteoglycans have revealed both the sophis-
tication of these regulatory proteins and the challenges that
remain in uncovering the entirety of their biological
functions. This review aims to summarize the multiple
functions of proteoglycans with special emphasis on their
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 815, project A5; SCHA 1082/2-1; Excellence Cluster ECCPS)
and the Else Kröner-Fresenius-Stiftung.
L. Schaefer (*)
Pharmazentrum Frankfurt/ZAFES,
Institut für Allgemeine Pharmakologie und Toxikologie,
Klinikum der Goethe-Universität Frankfurt am Main,
Theodor-Stern-Kai 7,
60590 Frankfurt am Main, Germany
e-mail: Schaefer@med.uni-frankfurt.de
R. M. Schaefer
Department of Medicine D, University Hospital of Münster,
Albert-Schweitzer-Strasse 33,
48149 Münster, Germany
intricate composition and the newly described signaling
events in which these molecules play a key role.
Keywords Chondroitin sulfate . Heparan sulfate .
Keratan sulfate . Small leucine-rich proteoglycans .
Glomerular basement membrane
Introduction
Proteoglycans (PGs) are biological molecules composed of
a specific core protein substituted with covalently linked
glycosaminoglycan (GAG) chains. Hyaluronan (HA) is an
exception to this definition, as it lacks a protein core. GAGs
are linear, sulfated, negatively charged polysaccharides,
which can be divided into two classes, namely (1) sulfated
GAGs comprising chondroitin sulfate (CS), dermatan
sulfate (DS), keratan sulfate (KS), heparin, and heparan
sulfate (HS), and (2) non-sulfated GAGs such as HA. GAG
chains are made up of disaccharide repeating regions
containing acetylated amino sugar moieties (N-acetyl-
galactosamine or N-acetyl-glucosamine) and mainly uronic
acid (D-glucoronic acid or L-iduronic acid). By contrast, KS
GAGs are based on repeating disaccharides containing
galactose (−4 N-acetyl-glucosamine-β1,3-galactose-β1).
The sulfated GAGs (CS, DS, and HS) are linked to their
respective protein cores via serine residues. KS can be
synthesized on N-linked oligosaccharides and on serine/
threonine O-linked oligosaccharides, which are distinct
from the linkage regions of all other GAGs. HS and
heparin also contain N-sulfate residues (Bulow and Hobert
2006; Esko and Lindahl 2001; Gandhi and Mancera 2008;
Iozzo 1998; Kjellen and Lindahl 1991; Lander and Selleck
2000; Oldberg et al. 1990; Perrimon and Bernfield 2001;
Seidler and Dreier 2008).
238 Cell Tissue Res (2010) 339:237–246

Details concerning the synthesis and sorting of PGs have
been dealt with in earlier reviews (Kusche-Gullberg and
Kjellen 2003; Malavaki et al. 2008). After synthesis, some
PGs such as the small leucine-rich PGs (SLRPs; Schaefer
and Iozzo 2008) and the large molecular weight PGs,
versican (CS/DSPG) and aggrecan (CS/KSPG) are secreted
into the pericellular environment or are incorporated into
basement membranes, e.g., perlecan or agrin (both HSPGs;
Bi et al. 2005; Bix and Iozzo 2008). The syndecans, with a
core protein containing a transmembrane domain, are
associated with the cell membrane (Alexopoulou et al.
2007; Couchman 2003; Filmus et al. 2008), and the
glypicans are linked to the cell membrane by glycosyl-
phosphatidylinositol linkages. Some PGs, such as serglycin
(CS/HSPG), which is mainly found in hematopoietic and
endothelial cells, also have intracellular functions (Kolset
and Tveit 2008; Pejler et al. 2009; Perrimon and Bernfield
2001; Prydz and Dalen 2000; Fig. 1). In addition to those
PGs that are widely expressed in many tissues (e.g.,
decorin, versican), some appear to be tissue-specific, such
as brevican, neurocan, neuroglycan C (all CSPGs), and
phosphacan (CS/KSPG, a splice variant of the receptor-like
protein tyrosine phosphatase-β), found mainly in the
central nervous (CNS) system, which is particularly rich
in CSPGs (Haddock et al. 2007; Kwok et al. 2008;
Sugahara and Mikami 2007). Thus, the enormous molec-
ular diversity of PGs resulting from the various combina-
tions of protein cores substituted with one (e.g., decorin) or
more GAG chains of various subtypes (e.g., aggrecan with
ca. 100 CS and 30 KS) provides the structural basis for the
multitude of their biological functions.
The useful nomenclature provided by Iozzo and
Murdoch (1996) dividing extracellular PGs into SLRPs
and the heterogeneous group of modular PGs, charac-
terized by the assembly of various protein modules, has
stood the test of time. However, as our knowledge of
PG biology has expanded markedly, and as a host of
new members of this multifunctional family have since
been discovered, a more comprehensive classification
would be to group PGs according to the properties of
their core proteins and to take into account their
localization, size, and modular composition in addition
to the type of GAG carried by the protein core. Such an
approach would lead to a classification consisting of
three major PG families: 1) SLRPs, 2) modular PGs,
and 3) cell-surface PGs (Fig. 1). However, we are aware
that this classification is not free of overlapping, such as
the SLRP nyctalopin can also be classified as a member of
the cell-surface PGs.
Small leucine-rich PGs
SLRPs are characterized by a protein core with leucine-rich
repeats (LRRs), the presence of N-terminal cysteine clusters
and “ear repeats” (classes I–III), and at least one GAG side
chain (Huxley-Jones et al. 2007; Iozzo 1998; Iozzo 1999;
McEwan et al. 2006; Schaefer and Iozzo 2008). Based on

Fig. 1 Classification of proteo-

glycans (PGs) based on their
location and binding. The het-
erogeneous group of PGs in-
clude those of the extracellular
matrix, such as small leucine-
rich PGs (SLRP; e.g., decorin)
and modular PGs. Modular PGs
are divided into hyalectans
(hyaluronan- and lectin-binding
PGs) and the non-hyaluronan-
binding PGs of the basement
membrane. The third group of
cell-surface PGs encompasses
mainly the membrane-spanning
syndecans (e.g., syndecan-4) and
the glycosylphosphatidylinositol-
anchored glypicans (e.g.,
glypican-1). Serglycin is an
intracellular PG found in
hematopoietic and endothelial
cells
Cell Tissue Res (2010) 339:237–246 239

typical characteristics, such as conservation and homology
at the protein and genomic level, cysteine-rich regions, and
chromosomal organization, the family of SLRP is divided
into five sub-families, including the traditionally defined
classes I–III and the non-canonical classes IV and V
(Table 1). Some molecules (e.g., asporin) appear to be
non-classical PGs, but as they share some typical features
of PGs, they are included into the SLRP family. Detailed
structural characteristics of SLRPs have been provided in a
recent review (Schaefer and Iozzo 2008). Based on genome
database analysis of the ear-containing LRR C-terminal
capping motif, a yet uncharacterized new SLRP on the
human X chromosome (ECMX) has been identified (Park
et al. 2008). This approach might provide a useful tool to
expand the SLRP family further.
The LRRs of the protein cores, which are considered to
be particularly relevant for protein-protein interactions,
have established SLRPs as important regulators of various
biological processes (Brandan et al. 2008; Chakravarti
2002; Danielson et al. 1999; Kao and Liu 2002; Roughley
2006; Schaefer and Iozzo 2008; Young et al. 2006). The
involvement of GAG chains, however, has not been
investigated in greater detail. In addition to consolidated
biological functions, e.g., binding to collagen I and
inhibition of cell growth, shared by class I–III and podocan
(Shimizu-Hirota et al. 2004) or modulation of bone
morphogenetic protein activity shared by biglycan and
Tsukushi (Chen et al. 2004; Moreno et al. 2005; Ohta et al.
2004), SLRPs have molecule-specific functions that are
executed in a cell-specific manner. Lessons from mice
deficient in SLRPs indicate further functional overlap
within this family (Ameye and Young 2002; Bi et al.
2007; Schaefer et al. 2002). Major functions of decorin
(CS/DS PG), the prototype member of SLRPs, are
summarized in Table 2 (for further details, we refer to
more extensive reviews: Brandan et al. 2008; Chakravarti
2002; Danielson et al. 1999; Kao and Liu 2002; Nikitovic
et al. 2008; Roughley 2006; Schaefer and Iozzo 2008;
Young et al. 2006).
Decorin, biglycan (CS/DS PG), and fibromodulin (KS
PG) are capable of binding, albeit with low affinity, all
three isoforms of transforming growth factor-β (TGF-β;
Hildebrand et al. 1994). Therefore, the biological implica-
tions of interacting with TGF-β, in order to develop anti-
fibrotic therapies, have been investigated intensively (Border
et al. 1992; Schaefer et al. 2001, 2002; Yamaguchi et al.
1990). Several possible interactions of decorin with TGF-β
have been postulated, such as direct binding and inactivation,
sequestration into the extracellular matrix (ECM) via decorin
bound to TGF-β (Kresse and Schonherr 2001) and/or
decorin-mediated interference with TGF-β signaling either
through phosphorylation of Smad2 (Abdel-Wahab et al.
2002) or LRP-1, a cell-surface receptor for decorin (Brandan
et al. 2008). However, in the light of the complexity of the
interaction of decorin with the ECM and various cellular
elements, involving (to date) four different tyrosine kinase
receptors (Table 2), the utilization of decorin-based therapy
for suppressing fibrogenesis might be less straightforward
than initially thought.
Our current knowledge regarding the fascinating phe-
nomenon that SLRPs, initially thought of as mere structural
components of the ECM, might directly regulate cellular
processes by receptor-mediated signaling has been summa-
rized in recent reviews (Brandan et al. 2008; Goldoni and
Iozzo 2008; Schaefer and Iozzo 2008). Particularly note-
worthy, SLRPs are capable of interacting with some LRR
receptors and their respective adapter molecules, which are
involved in pathogen recognition. Biglycan, upon its
release from the ECM or by secretion from macrophages,
acts as an endogenous ligand of Toll-like receptor 2 (TLR2)
and TLR4 (Schaefer et al. 2005), whereas lumican (KS PG)
is involved in the presentation of bacterial lipopolysacchar-
ides to TLR4/CD14 (Wu et al. 2007; Fig. 2). Thus, SLRPs
appear either to act as pathogen-associated molecular

Table 1 Classification of small leucine-rich proteoglycans (ECMX uncharacterized new small leucine-rich proteoglycan on the human X
chromosome, ECM2 extracellular matrix protein 2, PRELP proline/arginine-rich end leucine-rich repeat protein)

Class I Class II Class III Class IV Class V

Decorin (CS/DS, Fibromodulin (KS, Epiphycan (CS/DS, 36) Chondroadherin (KS, Podocan (70 kDa)
36 kDa) 42 kDa) 36 kDa)
Biglycan (CS/DS, Lumican (KS, 38 kDa) Opticin (35–45 kDa) Nyctalopin (50 kDa) Podocan-like protein 1
38 kDa) (57 kDa)
Asporin (42 kDa) PRELP (KS, 44 kDa) Osteoglycan (KS, Tsukushi (40 kDa)
35 kDa)
ECM2 (77 kDa) Keratocan (KS, 38 kDa)
ECMX (64 kDa) Osteoadherin (KS,
42 kDa)

The type of the glycosaminoglycan provided only by classical proteoglycans (CS chondroitin sulfate, DS dermatan sulfate, KS keratan sulfate) and
the approximate molecular weight of protein core (kDa) without posttranslational modifications are given
240 Cell Tissue Res (2010) 339:237–246

Table 2 Decorin: biological functions and receptors (TGF-β transforming growth factor-β, EGF epidermal growth factor, IGF-I insulin-like
growth factor-I, LRP-I low-density lipoprotein receptor-related protein-I)

Major regulatory functions Receptors

Collagen fibrillogenesis (Danielson et al. 1997; Ferdous et al. 2008)

Tumor growth and metastatic spreading (Goldoni and Iozzo 2008)
Angiogenesis (Jarvelainen et al. 2006)
TGF-β inhibition and sequestration (Border et al. 1992; Schaefer et al.
2001; Yamaguchi et al. 1990)
Renal and pulmonary fibrosis (Kolb et al. 2001; Schaefer et al. 2002)
Muscular development and dystrophy (Brandan et al. 2008)
Fibrillin-1 synthesis (Schaefer et al. 2007)
Wound healing (Jarvelainen et al. 2006)
Myocardial infarction (Weis et al. 2005)
Lyme disease (Brown et al. 2001)
EGF receptor (Goldoni and Iozzo 2008; Schaefer and Iozzo 2008);
c-met (Goldoni et al. 2009)
IGF-I receptor (Schaefer and Iozzo 2008; Schonherr et al. 2005)
LRP-I (Brandan et al. 2006)
IGF-I receptor (Schaefer and Iozzo 2008; Schonherr et al. 2005)
LRP-I (Brandan et al. 2006)
IGF-I receptor (Schaefer and Iozzo 2008; Schonherr et al. 2005)

pattern (PAMP) analogs or to be involved in the presenta-
tion of PAMPs to the receptor complex, thereby being part
of the innate immune response. Furthermore, SLRPs may
mediate neutrophil infiltration by forming an immobilized
chemokine gradient within inflamed tissues (Carlson et al.
2007; Fig. 2). Additional studies addressing the binding
mechanisms are required if we are to understand and
pharmacologically influence SLRPs-triggered TLR-
signaling in PAMP-mediated and non-infectious inflamma-
tory disorders.
Human diseases associated with mutations in SLRP
genes are mostly related to abnormalities of the eye.

Fig. 2 Impact of SLRPs on the

regulation of inflammation. Up-
on proteolytic release from the
extracellular matrix during tis-
sue stress or injury or after
secretion from activated macro-
phages, biglycan acts as an
endogenous ligand of Toll-like
receptor 2 (TLR2) and TLR4 in
macrophages (LRR leucine-rich
repeat, CS/DS chondroitin sul-
fate/dermatan sulfate, LPS bac-
terial lipopolysaccharides, MD2
myeloid differentiation factor-2).
It has been shown to stimulate
the synthesis of tumor necrosis
factor α (TNFα) and
macrophage-inflammatory
protein-2 (MIP-2) and also to
boost the inflammatory response
in an autocrine and paracrine
manner. By contrast, lumican
binds LPS and facilitates its
presentation to TLR4/CD14.
Moreover, it creates a chemo-
kine gradient for infiltrating
neutrophils by immobilizing
chemokines (e.g., mouse KC-
CXCL1; KC)
Cell Tissue Res (2010) 339:237–246
Truncated forms of decorin lacking the ear repeat cause
congenital dystrophy of the cornea by altering the orthog-
onal arrangement of corneal collagen fibrils required for
transparency. Myopia is caused by loss-of-functional
mutations in a number of SLRP genes, including lumican,
fibromodulin, PRELP, and opticin. Missense and frame
shift mutations in the keratocan gene causes cornea plana
with subsequent hyperopia, astigmatism, and poor acuity.
Mutations in the nyctalopin gene cause X-linked night
blindness.
Disruptions of SLRP genes in mice have revealed
various clinical phenotypes based on abnormal collagen
fibrillogenesis. Decorin deficiency is associated with
enhanced skin fragility similar to that in Ehlers-Danlos
syndrome in humans, whereas lack of biglycan causes
osteoporosis and spontaneous aortic dissection (in male
animals only). Disruption of the fibromodulin gene
leads to ectopic tendon ossification and osteoarthritis.
Mice deficient in lumican suffer from progressive
corneal opacification.
Hyaluronan
HA is a non-sulfated high-molecular-weight GAG not
linked to a protein core and is composed of repeating
disaccharides in which N-acetylglucosamine and glucur-
onic acid are combined by β-1,3 and β-1.4 linkage
(Itano 2008; McDonald and Hascall 2002). Being abun-
dant in most tissues, HA is a structural component of the
ECM but can also be found intracellularly (Hascall et al.
2004). It is synthesized by membrane-bound HA syn-
thases (HAS1, HAS2, HAS3; Weigel and DeAngelis
2007). Catabolism of HA is mainly mediated by several
hyaluronidases of which six members (HYAL1–4, PH-20,
HYALP1) have been described in humans so far (Itano
2008). HA binds to a variety of proteins and PGs, denoted
as hyalectans (HA- and lectin-binding PGs; Day and
Prestwich 2002; Fig. 1). Via interaction with a variety of
receptors, such as CD44, RHAMM (receptor for HA-
mediated motility expressed protein), LYVE-1 (lymphatic
vessel endothelial HA receptor-1, and HARE (HA recep-
tor for endocytosis, stabillin-2), HA is capable of acting as
a signaling molecule (Jiang et al. 2007), triggering diverse
signaling pathways, such as Ras, mitogen-activated pro-
tein (MAP) kinases, c-Src, PI3kinase/Akt, and is involved
in the regulation of cell growth, differentiation, adhe-
sion, and motility, thereby influencing embryonic devel-
opment, tumorigenesis, atherosclerosis, and lung and
kidney injury (Itano 2008; Jiang et al. 2007; Wight 2008).
The function of HA depends on its molecular size. As
opposed to the native form (>1000 kDa), lower-molecular-
weight fragments (<500 kDa), which accumulate during
241
tissue injury, interact with the TLR4 and TLR2 involving
MyD88-dependent signaling (Jiang et al. 2007). Thus,
degradation products of HA act as endogenous ligands of
innate immunity receptors, similar to descriptions for
biglycan (for further details, see Knudson and Knudson,
this issue).
Modular PGs
The modular PGs are a heterogeneous group character-
ized by the assembly of various protein modules in an
elongated and often highly glycosylated structure (Iozzo
and Murdoch 1996). This group is further divided into
two subfamilies of hyalectans (HA- and lectin-binding
PGs) and the non-HA-binding PGs (Iozzo 1998). Some
aspects regarding the tissue distribution of the modular
PGs, their major function, and related disorders are
summarized in Table 3.
Hyalectans
The family of hyalectans currently contains four mem-
bers: versican, aggrecan, neurocan, and brevican (Fig. 1,
Table 3). A shared feature of these PGs is a tridomain
structure consisting of a central domain that carries most
of the GAGs flanked by unique N- and C-terminal
globular regions with multiple motifs. The N-terminal
domain of hyalectans binds HA, and the C-terminal part
interacts with lectins. The length of the central domains
predicts a number of attachment size for GAGs from three
in brevican up to 100 in aggrecan (Iozzo 1998; Iozzo and
Murdoch 1996; Wu et al. 2005). Versican, the largest
member of hyalectans gene family, contains an
immunoglobular-like motif and two HA-binding PG
tandem repeats in its N-terminal region followed by an
alternatively spliced GAG-chain-binding region resulting
in the V0, V1, V2, and V3 isoforms with 370-kDa, 263-
kDa, 180-kDa, and 74-kDa protein cores. The C-terminal
region of versican contains EGF-like repeats and a
complement-binding protein-like subdomain in addition
to the lectin-like motif (Wight 2008; Wu et al. 2005). This
complex structure, which allows versican to interact with a
host of ECM components and cell-surface proteins (e.g.,
HA, type I collagen, fibrillin-1 fibronectin, P- and L-
selectin, CD44, EGFR, integrin β1, TLR2; Kim et al.
2009; Wu et al. 2005), together with its wide expression
in a variety of tissues, makes versican a crucial
regulator of cell-matrix interactions (Table 3; Iozzo
1998; Wight 2008). Molecule-specific differences within
the tridomain structure of aggrecan, neurocan, and
brevican are discussed in other reviews (Iozzo 1998;
242 Cell Tissue Res (2010) 339:237–246

Table 3 Modular proteoglycans (AChR acetylcholine

acetylcholine receptor,
receptor, ASMC
ASMC arterial
extracellular
smooth muscle
matrix,cell,
HSBM heparan
basement
sulfate,
membrane,
MMP matrix
CNS central
metalloprotei-
nervous
system, smooth
arterial CS chondroitin
muscle sulfate,
cell, BMDSbasement
dermatanmembrane,
sulfate, ECM
CNSextracellular
central nase,
matrix,
NAHS notheparan
applicable,
sulfate,
PGMMP
proteoglycan,
matrix metalloproteinase,
SPARC secreted protein,
NA not
applicable,
nervous system,
PG proteoglycan,
CS chondroitin
SPARC
sulfate,
secreted
DS dermatan
protein, acidic
sulfate,
andECM
rich in cysteine,
acidic and
TLRrich
Toll-like
in cysteine,
receptor)
TLR Toll-like receptor)

Modular Proteoglycan Protein core Tissue distribution Major functions Human disease caused
PGs (GAG) (approximate by PG gene mutation
kDa)a

Hyalectans/ Versican (CS/ 265–370 Blood vessels, CNS, Regulation of cell (mainly ASMC) NA
lecticans DS; V0, V1, skin, cartilage adhesion, migration and proliferation,
V2, V3 ECM assembly, fibrillogenesis of
isoforms) elastic fibers; endogenous ligand of
TLR2
Aggrecan (CS/ 220 Cartilage, CNS, Regulation of cartilage development, Spondyloepiphyseal
KS) blood vessels growth and homeostasis dysplasia
Neurocan (CS) 245–136 CNS Inhibition of neuronal attachment and NA
Brevican (CS) 100 CNS neurite outgrowth
Non- Perlecan (HS/ 400–467 BM, cartilage, Signaling, pro-angiogenic (proliferative Dyssegmental
hyaluronan- CS) connective tissue and migratory pathways), collagen dysplasia, Silver-
binding stromas fibrillogenesis, apoptosis; C-terminal Handmacher type;
PGs domain: Endorepellin, anti-angiogenic Schwartz-Jampel
syndrome
Agrin (HS) 212 BM, neuro-muscular Modulator of synaptogenesis, AChR- NA
junctions, immune aggregation, T-cell signaling, skele-
system, chondro- togenesis
cytes
Testicans (1–3), 45 Seminal fluid, brain, Neuronal attachment, MMP and NA
BM-40/ cartilage cathepsin L inhibition
SPARC/osteo-
nectin family
(CS/HS)
Phosphacan 200–250 CNS Cell-specific regulation of neurite NA
(CS/KS) outgrowth
Collagen IX Three Cartilage, Regulation of cartilage collagen fibril Chondro-dysplasias,
(CS/DS) polypeptides intervertebral disc, formation, stabilization of cartilage multiple epiphyseal
(65, 84, 72) embryonic tissue dysplasia,
(corneal stroma, intervertebral disc
skin, CNS) degeneration
Collagen XV 225–250 Vascular, neuronal, Responsible for capillary integrity; NC1 NA
(CS) mesenchymal, BM domain: Endostatin-like (Restin), anti-
zone angiogenic
Collagen XVIII 187 BM zone Effects on growth factors and Knobloch syndrome,
(HS) angiogenesis, cell adhesion, motility, BM broadening
apoptosis; NC1 domain: Endostatin,
anti-angiogenic
a
Size of individual protein core does not include posttranslational modifications

Kwok et al. 2008; Roughley 2006). Aggrecan, expressed
mainly in cartilage and brain, exists exclusively in the
form of aggregates stabilized by a link protein and
composed of HA and up to 100 aggrecan molecules
(Roughley 2006). Proteolytic cleavage of the aggrecan
protein core by aggrecanases and matrix metalloproteinase
generates fragments of various sizes, which, depending on
the site of cleavage, can be retained and accumulate in
cartilage (Huang and Wu 2008; Roughley 2006). Muta-
tions in human, mouse, and chicken aggrecan genes result
in chondrodysplasias (Gleghorn et al. 2005; Li et al. 1993;
Watanabe et al. 1994). Neurocan and brevican are two
hyalectans of the CNS and exist either in a full-length PG
form or in a form lacking the N-terminus and the GAG-
binding domain because of proteolytical processing. There
are two PG isoforms of brevican: a longer secreted form
and a glycosylphosphatidylinositol (GPI)-anchored form
without the carboxyl lectin-like and EGF-like domains
(Iozzo 1998; Kwok et al. 2008; Rauch 2007; Schwartz and
Domowicz 2004).
The members of the non-HA-binding PGs are listed in
Table 3 (Briggs et al. 1994; Bruckner et al. 1988; Olsen
1997). Further details are described in more extensive
reviews (Bix and Iozzo 2008; Carter and Raggio 2009;
Farach-Carson and Carson 2007; Iozzo 1998, 2005; Iozzo
and Murdoch 1996; Lin 2004; Myers et al. 2007; Rodgers
Cell Tissue Res (2010) 339:237–246
et al. 2008). Here we focus on HSPGs of the glomerular
basement membrane underlying their unique role in
glomerular filtration.
Basement membrane PGs
Basement membranes are thin layers of specialized ECM
and are formed in the interface between parenchymal cells
and surrounding connective tissue. Collagen type IV
together with laminin, nidogen, fibulin, dystroglycan, and
HSPGs are major constituents (Erickson and Couchman
2000). Specialized basement membranes, such as those in
the renal glomerulus, are highly differentiated displaying
unique structures and functions. The glomerular basement
membrane (GBM) serves as a charge-selective semi-
permeable filtration barrier. The negative charge of the
GBM has been attributed to the presence of HSPGs
(Kanwar and Farquhar 1979). Three distinct HSPGs have
been identified within the GBM: agrin, perlecan, and
collagen XVIII.
Agrin, is primarily produced by podocytes and is the
most abundant HSPG of the adult GBM in humans. Its
protein core (212 kDa) has four HS side chains and four N-
linked oligosaccharide chains. In the GBM, agrin binds to
laminin via its globular domain and to dystroglycan and
integrin receptors through its C-terminal end and is thought
to be an integral part of the molecular complex linking
podocytes to the GBM. Homozygous agrin-null mice die at
birth because of paralysis resulting from the absence of
neuromuscular junctions (Lin et al. 2001). Conditional
knockout mice, in which agrin is ablated in podocytes, have
demonstrated that agrin contributes to the anionic charge of
the GBM but is not needed for glomerular function (Harvey
et al. 2007).
In the glomerulus, perlecan is produced by endothe-
lial cells and is present in the GBM primarily during
development, whereas in adults, it is predominantly
found in the mesangial matrix and in Bowman’s
capsule. The core protein of perlecan (400–467 kDa)
is composed of five domains suggesting that the protein
core itself has multifunctional properties. The HS side
chains have on average a molecular mass of 380 kDa.
Homozygous perlecan-deficient mice die in utero or
shortly after birth with basement membrane disruptions
in areas of increased mechanical strain (Costell et al.
1999). Homozygous mice with an exon-specific mutation
that removes the HS-binding sites have no renal pheno-
type (Lin et al. 2001).
Collagen XVIII, considered to be a hybrid collagen-PG,
has a central triple-helical collagenous domain interrupted
by non-collagenous sequences, which have three binding
sites for HS-side chains. In the adult glomerulus, collagen
243
XVIII is localized primarily in the mesangial matrix and in
the basement membrane of Bowman’s capsule. Collagen
XVIII-null mice display broadening of their basement
membranes in various organs, including the kidney, and
suffer from mesangial expansion and reduced renal function
(Iozzo 2005).
Cell-surface PGs
The cell-surface PGs include two major groups: (1)
membrane-spanning (e.g., syndecans) and (2) GPI-linked
PGs (e.g., glypicans; Fig. 1). Syndecans and glypicans
are the major HSPGs on the cell surface with HS acting as
a co-receptor facilitating ligand encounters with signaling
receptors (Bernfield et al. 1999; Park et al. 2000). Most
intracellular pathogens use cell-surface HSPGs for attach-
ment, invasion, transmission, or host defense evasion by
binding to the soluble ectodomain of HSPGs (Chen
et al. 2008). Syndecans, betaglycan, which is involved in
TGF-β-signaling, CD44v3, and three PGs of the CNS
(neuroglycan C, NG2, and RPTP-ζ) belong to the
membrane-spanning PGs. The syndecans, with four
members cloned in mammals, are type I transmembrane
proteins mostly substituted with HS GAG chains.
Syndecan-1 is present at early stages during development
and on epithelial and cancer cells in adults. Syndecan-2 is
distributed in mesenchymal tissues, liver, and neuronal
cells. Syndecan-3 is mainly associated with neural tissues,
whereas syndecan-4 is ubiquitously distributed (Bernfield
et al. 1999) (Couchman 2003; Gotte 2003; Lin 2004;
Rodgers et al. 2008). The biological functions of synde-
cans, other than the GAG-mediated binding of ligands on
the cell surface, are mainly defined by their core proteins.
There is growing evidence for the involvement of
syndecans in complex signaling events through which
they regulate cell proliferation, differentiation, adhesion,
and migration (for further details of syndecans, see J.
Couchman, this issue).
The group of GPI-linked cell-surface PGs includes
the glypicans and a splice form of brevican (CSPG)
lacking the carboxyl lectin-like and EGF-like domains.
In mammals, there are six members in the glypican
family characterized by HS GAGs linked to a protein
core of 60–70 kDa with 14 highly conserved cysteine
residues. In adults, glypican-1 is ubiquitously expressed,
whereas glypican-6 is found mainly in the heart, kidney,
liver, ovaries, and intestine. By contrast, glypican−3, −4,
and −5 are located exclusively in the CNS. Glypican-2
is present in the CNS only during embryonic develop-
ment. Glypicans are involved in the regulation of
various signaling pathways including that of Wnt,
fibroblast growth factor, Hedgehog, bone morphogenic
244
protein, Slit, and insulin-like growth factor signaling
(Filmus et al. 2008; Fransson et al. 2004; Rodgers et al.
2008). Some of these pathways appear to be differentially
regulated by glypicans in various species (Beckett et al.
2008). In humans, mutations in the glypican-3 gene cause
Simpson-Golabi-Behmel syndrome mainly characterized
by overgrowth (Pilia et al. 1996).
Heparin vs. HS
Heparin is exclusively synthesized by connective-tissue-
type mast cells as serglycin PG. During its biosynthesis,
heparin undergoes extensive sulfation and uronic acid
epimerization, such that more than 80% of the N-acetyl-
glucosamine residues are N-deacetylated and N-sulfated,
and more than 70% of the uronic acid is converted to
iduronic acid. HS on the other hand is a PG-associated
glycosaminoglycan, similar to heparin in its basic design,
but features less epimerization to iduronate, lower density
of N- and O-sulfation, higher N-acetylation, and greater
asymmetry of sulfation and charge density along the
polymer. HS made by virtually all cells and also contains
some anticoagulant activity, but typical preparations are
much less active than heparin (Hardingham and Fosang
1992).
Perspectives
Over the last decade, the discovery of a plethora of
functional roles of PGs has made their study an
emerging and promising field with great functional and
regulatory significance in all aspects of cell biology and
human diseases. The intricate structure of the diverse
core proteins anchoring one or more glycosaminoglycan
chains of various subtypes and giving rise to an
enormous molecular diversity provides the structural
basis for a multitude of biological functions, such as the
organization of ECM assembly and the regulation of
growth factor and cytokine signaling. Furthermore, PGs
themselves appear to bind to many cell-surface receptors
with high specificity, thereby activating signaling path-
ways that control cell proliferation, differentiation,
adhesion, and migration. These interactions are essential
for organ integrity and function and might represent
interesting drug targets for disrupting pathological
mechanisms that lead to aging, inflammation, fibrosis,
and malignant diseases.
Acknowledgements We thank Chad Casey for his support with the
graphical design.
Cell Tissue Res (2010) 339:237–246
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