2975
Journal of Cell Science 107, 2975-2982 (1994)
Printed in Great Britain © The Company of Biologists Limited 1994
COMMENTARY
Function of the syndecans - a family of cell surface proteoglycans
Klaus Elenius and Markku Jalkanen*
Turku Centre for Biotechnology, Tykistökatu 6, Biocity, PO Box 123, FIN-20521 Turku, Finland
*Author for correspondence
INTRODUCTION
Cell surface proteoglycans are membrane-anchored glycoproteins that contain covalently linked glycosaminoglycan sidechains. They interact via their extracellular part with various
effector molecules such as growth factors, extracellular matrix
components, other cell surface molecules and proteins
involved in the regulation of blood coagulation. This together
with numerous examples of strictly regulated expression
patterns during embryogenesis and malignant transformation
has lead to the attribution of several specific functions to cell
surface proteoglycans. Molecular biology techniques that have
made it possible to identify and characterize individual proteoglycans, may also turn out to be crucial in determining the
relevance of the several suggested functions in vivo. This
review will mainly focus on the functional aspects of one wellcharacterized group of cell surface proteoglycans, the members
of the syndecan gene family.
STRUCTURE OF THE SYNDECAN GENE FAMILY
During the last decade the group of cloned cell surface proteoglycans has expanded to consist of more than ten structurally
and functionally different members (Fig. 1). Many of these
molecules were primarily identified as glycoproteins without
glycosaminoglycan (GAG) side-chains. Only more recent
experiments have revealed their occasional (‘part-time’)
existence also in a ‘true’ proteoglycan form, carrying heparan
sulfate and/or chondroitin sulfate side-chains. The first
molecules known to be cell surface proteoglycans at their time
of molecular cloning have recently been classified under the
term ‘syndecan gene family’ (Bernfield et al., 1992). The four
characterized family members are syndecan-1 (syndecan;
Saunders et al., 1989), syndecan-2 (fibroglycan; Marynen et
al., 1989), syndecan-3 (N-syndecan; Carey et al., 1992; Gould
et al., 1992) and syndecan-4 (amphiglycan or ryudocan; David
et al., 1992; Kojima et al., 1992b). All syndecans are anchored
to plasma membrane via a 24-25 amino acid long hydrophobic transmembrane domain, in contrast to another type of cell
surface proteoglycans that attaches to cell membrane using a
glycosyl-phosphatidyl-inositol linkage (e.g. glypican and cerebroglycan; David et al., 1990; Stipp et al., 1994; see Fig. 1).
The cytoplasmic domain is relatively short (28-34 amino acids)
but it contains four tyrosine residues (one at the border between
transmembrane and cytoplasmic domains) that are strictly
conserved among all the family members. This has lead to
speculation that the cytoplasmic domain could function as a
target for intracellular or membrane-attached tyrosine kinases
and thus possibly mediate a specific signal triggered by interactions between syndecan’s ectodomain and some extracellular effector molecule(s). It could also be suggested that a cell
might regulate adhesive properties of the ectodomain through
a conformational change achieved by phosphorylation of the
cytoplasmic domain. However, no biochemical data indicating
that phosphorylation of syndecans would indeed happen have
been reported so far.
While the transmembrane and cytoplasmic domains share a
high degree of homology, the extracellular ‘ectodomains’ of
the members of the syndecan gene family are the most dissimilar regions (Fig. 2). The GAG chains attach to serine
residues of Ser-Gly pairs, which are usually flanked by acidic
amino acids. Syndecan-1 bears variable amounts of chondroitin sulfate in addition to heparan sulfate chains but
syndecan-2, -3 and -4 probably contain solely heparan sulfate,
although as yet they have only been characterized from few
cell lines. The functional contribution of the chondroitin sulfate
chains still remains to be elucidated.
The most obvious differences between syndecans include
(together with differences in distribution) the subclassification of the family depending on the existence of GAG binding
sites either at both ends of the ectodomain (syndecan-1 and 3) or at the distal part only (syndecan-2 and -4) and a relatively long Thr-Ser-Pro-rich area in the middle of syndecan3’s ectodomain. The division of syndecans to molecules
having either one or two clusters of GAG attachment sites in
relation to their putative binding properties has made it
tempting to think that the structure of syndecan-1 and -3
would be better constructed for simultaneous binding of more
than one extracellular effector molecule than the structurally
more simple syndecan-2 and -4. This theory is supported by
the finding that syndecan-1 molecule can indeed attach to a
matrix protein (type I collagen or fibronectin) and to fibroblast growth factor-2 (FGF-2=bFGF) at the same time
(Salmivirta et al., 1992). On the other hand, a recent publication suggests that all the heparan sulfate side-chains of
mouse syndecan-1 reside at the distal GAG binding sites of
the core protein (Kokenyesi and Bernfield, 1994), making the
Key words: angiogenesis, extracellular matrix, fibroblast growth
factor, heparan sulfate, tumorigenesis
2976 K. Elenius and M. Jalkanen
proximal (chondroitin sulfate) GAG chains unnecessary in
this particular case. Future studies of the binding capabilities
of other syndecans (2-4) are expected to provide more information about the functional relevance of proximal sugar
chains in the near future.
One interesting feature common to syndecans is the presence
of dibasic sequences surrounded by acidic amino acids at the
border of transmembrane domains and ectodomains or within
the proximal ectodomain. These sites have been suggested to
be targets for serine proteases, releasing the ectodomains to
pericellular or extracellular space. In the case of syndecan-1,
this shedding of ectodomain from the surfaces of cultured cells
has been demonstrated (Jalkanen et al., 1987) but immunohistochemical studies on tissues cannot provide conclusive
evidence to show whether this shedding takes place in vivo.
One possibility is that cells anchored to the surrounding matrix
or to adjacent cells carry mainly intact syndecan molecules but
when cells are stimulated to migrate (e.g. during wound
healing or tumorigenesis; Elenius et al., 1991; Inki et al., 1991),
they loosen their attachment by cleaving the ectodomains with
the help of pericellular proteases.
Recently, the structure/function relationship of the heparan
sulfate side-chains of cell surface proteoglycans has received
increasing attention. Heparan sulfate is a heparin-like
molecule that is synthesized as a polymer of repeating disaccharide sequences of D-glucuronic acid and N-acetyl-D-glucosamine. The synthesis takes place within the Golgi
membranes after a core protein containing a relevant GAG
attachment site (a Ser-Gly pair plus appropriate flanking
sequences) is transported there from the endoplasmic
reticulum. Along with polymerization, the elongating GAG
chain is subjected to various modification steps catalyzed by
specific enzymes. Either the hexuronic or glucosamine units
may be sulfated at O or N residues and the D-glucuronic acid
epimerized to L-iduronic acid (Kjellén and Lindahl, 1991).
The extent and sequence of the modifications provide the
chain with short stretches having specific binding properties.
A well-known example is the pentasaccharide sequence of
heparin that has been described to selectively bind antithrombin-III (Lindahl et al., 1984). A few new studies have focused
on characterizing the FGF-2 binding sequence of heparan
sulfate/heparin and reduced the minimal required region to a
penta- (Guimond et al., 1993; Maccarana et al., 1993) or hexasaccharide (Habuchi et al., 1992; Tyrrell et al., 1993) containing N-sulfated glucosamine units and at least one 2-Osulfated iduronic acid. In the case of FGF-1 (aFGF) even a
specific tetrasaccharide sequence of heparin may be sufficient
to allow an interaction between the molecules (Mach et al.,
1993). One heparan sulfate chain may contain several interspersed FGF-2 binding sites and, interestingly, also sequences
that are inhibitory to the action of the growth factor (Guimond
et al., 1993). Furthermore, different members of the FGF
family seem to require specific heparan sulfate sequences
(Chernousov and Carey, 1993; Guimond et al., 1993) and a
single cell surface proteoglycan core protein may carry either
FGF-1- or FGF-2-specific heparan sulfate regions depending
on the growth factor available at different developmental
stages (Nurcombe et al., 1993). Although no detailed data
about the specific modification of the heparan sulfate chains
attached to syndecans exist, the glycosylation pattern (type,
length and number of GAG chains) of syndecan-1 has been
shown to be regulated according to the tissue in which it is
expressed (Sanderson and Bernfield, 1988; Salmivirta et al.,
1991), along with keratinocyte differentiation (Sanderson et
al., 1992) and in response to transforming growth factor-β
(TGF-β) treatment (Rapraeger, 1989). Supporting the functional importance of the structure of sugar chains, a differently
glycosylated form of syndecan-1 (no or undetectable amounts
of chondroitin sulfate) isolated from developing tooth mesenchyme has been shown to bind a matrix molecule tenascin
with clearly better affinity than a hybrid syndecan-1 (both
heparan and chondroitin sulfate chains) from cultured epithelial NMuMG cells (Salmivirta et al., 1991). Moreover,
Sanderson et al. (1994) have recently demonstrated that differences in the modification pattern of syndecan-1 GAG
chains is probably the reason why syndecan-1 from one
myeloma cell line binds type I collagen, but syndecan-1 from
another related line does not.
DISTRIBUTION
The expression pattern of syndecan-1 has been documented in
detail both in physiological and in some pathological conditions but reports about the distribution of other members of
the gene family are limited. Syndecan-1 is expressed in mature
tissues almost exclusively by epithelial cells, with the most
intense signals found from squamous and transitional epithelia
(Hayashi et al., 1987). One of the few exceptions to this is Blymphocytes, which are syndecan-1 positive when maturing
in bone marrow, lose syndecan-1 epitope when they are
released to circulation and regain it upon differentiation to
plasma cells within lymphoid tissue (Sanderson et al., 1989).
Syndecan-1 antigen cannot usually be detected at differentiated mesenchymally derived cells by immunohistochemistry,
although at the least fibroblasts, vascular smooth muscle cells
and endothelial cells are known to produce low amounts of
the molecule in cell culture (Cizmeci-Smith et al., 1992;
Elenius et al., 1992; Kojima et al., 1992b). However, during
embryogenesis, wound healing and carcinogenesis, the
expression pattern of syndecan-1 is not constant. The proliferating and condensing mesenchymal cells of several developing organs are transiently induced to express syndecan-1
(originally described for tooth organogenesis by Thesleff et
al., 1988). Similarly, endothelial cells, which are normally
syndecan-1 negative, activate their syndecan-1 synthesis when
they sprout and proliferate in the granulation tissue in
response to wound healing (Elenius et al., 1991). On the other
hand, transformation from normal epithelial cells to carcinomatous quickly proliferating cells is associated with a
decrease or loss of syndecan-1 expression both in vivo (Inki
et al., 1991) and in vitro (Leppä et al., 1991; Inki et al., 1992).
It has been suggested that growth factors could be responsible for the regulation of syndecan-1 expression (Vainio and
Thesleff, 1992). In accordance with this, a combination of
FGF-2 and TGF-β has been shown to induce syndecan-1 production in mesenchymal 3T3 fibroblasts (Elenius et al., 1992)
and platelet-derived growth factor (PDGF) in vascular smooth
muscle cells (Cizmeci-Smith et al., 1993). The only known
factor capable of down-regulating syndecan-1 expression in
adhesive cells is tumor necrosis factor-α (TNF-α), which has
a suppressive effect specifically on endothelial cells (V. Kain-
Function of syndecans 2977
ulainen et al., unpublished data). Interestingly, interleukin 6
(IL-6) has been shown to down-regulate syndecan-1
expression on B-lymphoid cells (Sneed et al., 1994), suggesting that the observed changes in syndecan-1 expression during
B-cell maturation (Sanderson et al., 1989) could also be
regulated by growth factors.
Syndecan-2 is mainly produced by mesenchymal cells
(hence its alternative name ‘fibroglycan’) and, in contrast to
syndecan-1, it is not expressed by epithelial cell lines
(Marynen et al., 1989; Lories et al., 1992). Syndecan-3 has
been characterized as a neural representative of the molecule
family (N-syndecan = neural syndecan; Carey et al., 1992) but
is also expressed, e.g., in some stratified epithelia and in differentiating cartilage (Gould et al., 1992). The expression
pattern of syndecan-4 is the most ubiquitous within the family,
which is why David et al. (1992) have also designated this
syndecan as ‘amphiglycan’, meaning a proteoglycan that is
expressed by both epithelial and fibroblastic cells.
Although, e.g., cultured vascular smooth muscle cells synthesize all four members of the syndecan family (Carey et al.,
1992; Kojima et al., 1992b; Cizmeci-Smith et al., 1993), the
otherwise clearly variable (at some developmental stages even
reciprocal) distribution implies differences also in the function
of the molecules. This is further supported by the findings that
there is specificity in the growth factors that are able to regulate
the expression of the family members (Cizmeci-Smith et al.,
1993), as well as in the binding properties of various syndecans
(Chernousov and Carey, 1993). For the lack of other than
descriptive reports from syndecan-2, -3 and -4, the next two
sections will mostly concentrate on functional aspects attributed to syndecan-1.
REGULATION OF CELL-MATRIX INTERACTIONS
Syndecan-1 has been suggested to function as a matrix receptor
transducing information between extracellular matrix and the
inside of the cell. This has been mainly based on studies
showing that syndecan-1: (i) binds several interstitial matrix
components through its ectodomain (Elenius et al., 1990); (ii)
is expressed at the basolateral surface of cultured epithelial
cells (Rapraeger et al., 1986) as well as in simple epithelia in
vivo (Hayashi et al., 1987); and (iii) is co-localized with
cytoskeletal actin filaments in polarized epithelial cells
(Rapraeger et al., 1986). Moreover, syndecan-1 has been
reported to be present at the site of initial matrix accumulation
in an early mouse embryo (Sutherland et al., 1991) and B-lymphocytes have been demonstrated to synthesize syndecan-1
only when in contact with extracellular matrix (Sanderson et
al., 1989). Transfection of a syndecan-1 cDNA construct into
NIH-3T3 fibroblasts (that normally produce low amounts of
cell surface syndecan-1) has further been shown to result in
increased binding of these cells to a substratum containing the
heparin-binding domain of fibronectin (Mali et al., 1993).
Increasing evidence is also accumulating to show that it is
possible to regulate cell morphology by changing the amounts
of syndecan-1 expressed at cell surfaces. Leppä et al. (1991)
have been able to demonstrate that hormone-transformed S115
epithelial cells down-regulate their syndecan-1 expression upon
conversion to fusiform morphology, but regain epithelioid
phenotype when they are transfected with a vector containing
syndecan-1 cDNA (Leppä et al., 1992). Carey et al. (1994)
transfected cultured Schwann cells with syndecan-1 cDNA
under a different promoter and, again, found changes in mor-
core protein ≅ 100 aa
Fig. 1. Structure of some cloned cell surface
proteoglycans. Length of core proteins has
GAG
been drawn to scale. The size of GAG
disulfide bridge
chains is not proportional to this. Some
suggested disulfide bridges are presented;
GPI
otherwise the molecules have been
anticipated to exist in extended
conformations. Syndecan-1, CD44 and
betaglycan may carry both heparan sulfate
(HS) and chondroitin sulfate (CS) GAG
chains. CD44 may contain several additional
GAG binding sites at alternatively spliced
exons. Diagrams of other syndecans than
syndecan-1 have been excluded. Core
proteins of syndecan-2 and -4 are one third
shorter than the core of syndecan-1 and
contain three to four GAG attachment sites
Name: invariant CD44
glypican thrombobetaglycan
NG2
syndecan-1 CSF-1
at the distal part of the ectodomain.
chain
modulin
Syndecan-3 is the longest syndecan,
contains at least seven possible GAG
GAG:
CS
CS/HS
HS/CS
CS
HS
CS
HS/CS
CS
attachment sites (distributed to both ends of
ectodomain) and has a specific threonineserine-proline-rich region within the ectodomain. The recently cloned cerebroglycan shares homology with glypican. Both are GPI-anchored
and three GAG binding sites are conserved between cerebroglycan and glypican. Cerebroglycan has three sites at the distal and two at the
proximal part of the ectodomain, respectively. The core of NG2 (over 2000 amino acids) has been cut to make the molecule fit in the figure.
GPI, glycosyl-phosphatidyl-inositol linkage; CSF-1, colony stimulating factor-1 (macrophage colony stimulating factor). The presented data
are based on reports by Miller et al. (1988), Marynen et al. (1989), Saunders et al. (1989), Bourin et al. (1990), David et al. (1990, 1992),
Brown et al. (1991), Nishiyama et al. (1991), Gould et al. (1992), Kojima et al. (1992b), Price et al. (1992), López-Cassilas et al. (1994) and
Stipp et al. (1994).
2978 K. Elenius and M. Jalkanen
phology, as well as enhanced spreading and reorganization of
cytoskeletal structures. Support for syndecan-1’s role as a
molecule that maintains epithelial morphology can also be
found in vivo from studies of organogenetic events demonstrating that syndecan-1 expression is usually associated with
epithelial phenotype or stability (for review see Bernfield et al.,
1992).
Although several publications have reported a co-localization of the syndecan-1 cytoplasmic domain and actin filaments
in polarized or spreading cells (Rapraeger et al., 1986;
Bernfield et al., 1992; Leppä et al., 1992; Carey et al., 1994),
Miettinen and Jalkanen (1994) were unable to demonstrate a
direct interaction between these molecules. Thus, it can be
speculated that syndecan-like molecules could function as coreceptors for other kinds of matrix receptors, like integrins
(Chun and Bernfield, 1993), making the matrix ligand more
available or changing its conformation (Fig. 3A). In this case
the signal transduction pathway to the inside of cell would be
mediated through the intracellular part of an integrin subunit
molecule. It has already been shown that the formation of focal
adhesions of fibroblasts cultured on fibronectin requires collaboration of both a cell surface heparan sulfate proteoglycan
and an integrin-type matrix receptor (Woods et al., 1986;
LeBaron et al., 1988). A recent study by Woods and Couchman
(1994) suggests that the syndecan type involved in this collaboration might be syndecan-4, which in contrast to syndecan1, syndecan-2 and glypican, is enriched and codistributed with
integrin subunits β1 and β3 in focal contacts. It will be interesting to see if future studies will reveal a direct interaction
between a heparan sulfate chain of a cell surface proteoglycan
and the extracellular part of an integrin subunit that is
analogous to that described below for cell surface proteogly-
can and the tyrosine kinase fibroblast growth factor receptor
(FGFR). However, at least in the case of syndecan-4, which
contains a specific cytoplasmic peptide sequence not found in
syndecans 1-3 (Woods and Couchman, 1994), the possibility
of an interaction between syndecan cytoplasmic domain and
cytoskeleton should not be forgotten.
Some aspects of the binding characteristics and expression
pattern of syndecan-1 also imply other functions than matrix
binding for the molecule. First, epithelial syndecan-1 has been
shown to interact in vitro with several interstitial matrix proteins
such as fibrillar collagens (Koda et al., 1985), fibronectin
(Saunders and Bernfield, 1988), thrombospondin (Sun et al.,
1989) and tenascin (Salmivirta et al., 1991) but not with the
basement membrane components type IV collagen or laminin
(Koda et al., 1985; Saunders and Bernfield, 1988), molecules
that are in vivo localized closest to the syndecan-1 molecules
expressed at basal surfaces of epithelial cells. Secondly,
syndecan-1 is also present at the lateral cell surfaces of simple
epithelia, as well as on the entire cell surfaces of stratified
epithelia (Hayashi et al., 1987), at sites that are not in contact
with extracellular matrix. This may imply that syndecan-1 participates in the formation of cell-cell adhesion either by selfassembly or with the help of some other molecules, but this has
not been experimentally tested. Interestingly, syndecan-3
isolated from neonatal rat brain has been shown not to interact
either with matrix proteins (fibrillar collagens, fibronectin) or
with basement membrane components (laminin, type IV
collagen) (Chernousov and Carey, 1993), further suggesting the
existence of functions other than matrix-anchoring for the
members of the syndecan gene family.
REGULATION OF CELL PROLIFERATION
Syndecan
types
ECTO
TM
CP
TOTAL
1 vs. 2
25
51
64
32
1 vs. 3
32
53
82
38
1 vs. 4
26
51
57
33
2 vs. 3
23
66
65
30
2 vs. 4
34
79
71
43
3 vs. 4
22
70
55
30
Fig. 2. Homology between rat syndecan-1 to -4. Rat is the only
species from which all four syndecans have been cloned. Maximal
percentages of identical amino acids from different domains and
from whole translated amino acid sequences are shown. The
schematic diagram at the top of the figure represents the structure of
rat syndecan-1.
Fig. 2The short vertical lines are at the sites of putative
GAG attachment.
the primary
structure of rat syndecan-3
Elenius Data
andabout
Jalkanen,
1994
are partial (Carey et al., 1992). Rat syndecan-1, -2 and -4 are
analyzed according to sequences published by Kojima et al. (1992b)
and by Pierce et al. (1992). ECTO, ectodomain (M); TM,
transmembrane domain ( ); CP, cytoplasmic domain ( ).
In 1991 two groups independently made an observation that
has since then drawn much attention to the biology of cell
surface proteoglycans. Rapraeger et al. (1991) and Yayon et
al. (1991) demonstrated that FGF-2 can neither bind to its
‘high-affinity’ receptors (FGFR-1) nor exert its growth stimulatory or differentiation inhibiting actions on cells made
deficient of adequately sulfated heparan sulfate proteoglycans.
The finding was soon confirmed by experiments taking
advantage of a cell-free system and showing that FGF-2 cannot
bind FGFR-1 in the absence of heparin (Ornitz et al., 1992).
This indicated that FGF-2, its tyrosine kinase receptor and a
heparan sulfate cell surface proteoglycan form a ternary
complex before the signal from growth factor is transduced
through multimerization and transphosphorylation of FGFRs
to inside the cell (Fig. 3B). Recently, Kan et al. (1993) have
shown that FGFR-1 contains a 13 amino acid long heparin
binding sequence that is required for the binding of growth
factor, suggesting that cell surface heparan sulfate proteoglycans indeed directly interact also with the tyrosine kinase
FGFRs. Furthermore, the minimal FGF-2 binding sequence of
heparin (penta- or hexasaccharide) is not sufficient to support
the biological activity of FGF-2 when given to cells in which
normal sulfation of heparan sulfate has been blocked by
chlorate treatment. Rather, a longer deca- or dodecasaccharide
with specific sulfation pattern is required (Guimond et al.,
1993; Ishihara et al., 1993). This indicates that part of the
deca/dodecasaccharide sequence of heparan sulfate would
Function of syndecans 2979
interact with FGF-2 and another part with tyrosine kinase
FGFR (Fig. 3B).
At the least syndecan-1 and -3 bind FGF-2 (Kiefer et al.,
1990; Elenius et al., 1992; Chernousov and Carey, 1993). The
fact that some member(s) of the syndecan family is (are)
expressed by virtually all adhesive cells makes it probable that
syndecans function as molecules augmenting FGF-2 action in
vivo. In accordance with this, the expression pattern of
syndecan-1 has been shown to correlate with distribution of
another member of FGF family (FGF-3 = int-2) at some developmental stages (Thesleff et al., 1988; Wilkinson et al., 1989).
Other candidates for the heparan sulfate FGF co-receptor
include betaglycan (Andres et al., 1992) and glypican (David
et al., 1990). Interestingly, it has also been reported that
although a total cell surface proteoglycan fraction isolated from
human fetal lung fibroblasts supports the interaction of FGF-2
with FGFR-1, immunopurified syndecan-1, syndecan-2 and
glypican from the same cells are unable to do so (Aviezer et
al., 1994). It should, however, be noted that the glycosylation
pattern of most cell surface proteoglycans, including syndecan1, is highly variable, depending on cell type and extracellular
factors (Sanderson and Bernfield, 1988; Rapraeger, 1989), and
minor differences in disaccharide sequences have already been
shown to result in remarkable changes in ligand specificity
(Guimond et al., 1993; Nurcombe et al., 1993; Sanderson et
al., 1994).
After the first reports of FGF-2, it has been demonstrated
that at least FGF-1, FGF-4, vascular endothelial cell growth
factor (VEGF) and heparin-binding epidermal growth factor
(HB-EGF) also need heparan sulfate for signalling (GitayGoren et al., 1992; Olwin and Rapraeger, 1992; Higashiyama
et al., 1993). Moreover, it seems that the requirement of
heparan sulfate is a property not only of FGFR-1 but of all
FGFRs (Mansukhani et al., 1992; Ornitz and Leder, 1992). The
putatively selective interactions of various syndecans with
these molecules are at the moment under investigation. The
finding that syndecan-3 binds FGF-2 but not FGF-1 suggests
that some specificity may indeed exist (Chernousov and Carey,
1993).
Another aspect that supports syndecan-1’s role as a participant in the regulation of cell proliferation is its changing
expression at different proliferative states. As described above,
in general terms normal cell growth is associated with
activated, and abnormal proliferation with suppressed,
syndecan-1 expression, respectively. One explanation for this
phenomenon could be that enhanced syndecan-1 production is
needed for control of growth factor-stimulated cell growth.
This theory is supported by cell culture experiments demonstrating that, although syndecan-like molecules are obligatory
for the action of some heparin-binding growth factors, overexpression of syndecan-1 leads to abrogation of the growthstimulatory effect of FGF-2 (Mali et al., 1993). This is in accordance with the findings that syndecan-1 isolated from human
fibroblasts antagonizes heparin/heparan sulfate-enhanced
FGF-2 interaction with tyrosine kinase receptor (Aviezer et al.,
1994). Another possibility is that syndecan-1-deficient cells
have simply lost a cell surface molecule, which anchors them
to the extracellular matrix and, thus, have changed their morphology and become free to divide and migrate. The mechanisms by which cell surface heparan sulfate molecules can
affect growth factor-regulated growth control may, in addition
to cell surface level, also include events taking place at pericellular/extracellular or intracellular compartments. Proteolytic
cleavage of syndecan ectodomains enables the translocation of
the ectodomains to the extracellular matrix where they could
have activities described for matrix heparan sulfate proteoglycans: i.e. to form a reservoir of FGFs (Gonzalez et al., 1990;
Klagsbrun, 1990), to control diffusion of FGFs (Flaumenhaft
et al., 1990) or to protect FGF-2 from proteolytic activation
(Saksela et al., 1988). Analogous to the reports about matrix
proteoglycan decorin, which inhibits the effects of TGF-β by
immobilizing the growth factor to extracellular matrix
(Yamaguchi et al., 1990), enhanced shedding of syndecans
might lead to functional inactivation of heparin-binding
effector molecules (Mali et al., 1993). It has been suggested
further that heparin-like molecules are transported to the
cytoplasm and the nucleus where they could have effects on
targeting the internalization of FGF/FGFR complexes (Reiland
A
B
FGF
Fig. 3. Syndecan-1 as a co-receptor for matrix and
FGF. (A) Syndecan-1 (left) binds the heparinbinding domain of fibronectin at the same time as
an integrin-type matrix receptor attaches to the
cell-binding domain. (B) Syndecan-1, tyrosine
kinase FGF-receptor and FGF form a ternary
complex. All these three components probably
interact directly with each other and this is required
for the biological activity of the growth factor. One
of the GAG chains of syndecan-1 is shown to bind
the second IgG domain of FGFR and an FGF
SIGNAL
molecule simultaneously. In both cases (A and B)
the signal from extracellular effector molecules to
SIGNAL
the inside of the cell is thought to be mediated by
the cytoplasmic domains of receptor molecules
other than syndecan-1 (arrows). Syndecan-1 can
also be immobilized to matrix simultaneously with
FGF-2 interaction (Salmivirta et al., 1992), possibly enabling activation of both types of signals (A and B) at the same time. Tyrosine kinase
FGF receptors in this diagram contain three extracellular IgG loops ( ) and a split intracellular tyrosine kinase domain (M).
B
⇓
F
A
⇓
2980 K. Elenius and M. Jalkanen
and Rapraeger, 1993), on signal transduction pathways, like
Ca2+ release (Galione et al., 1993) or on binding of transcription factors to DNA (Busch et al., 1992).
PROSPECTS
In spite of the expanding interest during recent years on the
functions of cell surface proteoglycans and syndecans, to gain
knowledge of the exact mechanisms by which they regulate
cell behaviour will still need a lot of work and perhaps
exploitation of more sophisticated molecular biology techniques. Future studies will certainly also be directed into new
fields such as the putative anticoagulant or angiogenic properties of syndecans expressed on endothelial cells (Kojima et al.,
1992a; Mertens et al., 1992) or the functions of syndecans as
receptors for various pathogenic agents (e.g. Herpes simplex
virus; Shieh et al., 1992). The ‘redundant’ or ‘superfluous’
expression of functionally similar molecules, which has been
suggested to have brought disappointments to many
researchers using transgenic knockout mice (Erickson, 1993),
may cause problems also in studies of a family of homologous
molecules such as the syndecans. Thus, experiments with
mutated, deleted or chimeric syndecan constructs could also be
expected to give answers to some of the existing questions,
especially if mutated molecules can replace the functional
syndecan during a restricted period of development.
Furthermore, the role of syndecans in many pathological
stages must also be studied by experimentation. Observations
that the level of syndecan-1 expression is associated with a histological degree of malignancy (Inki et al., 1991) or a clinical
outcome of human tumors (Inki et al., 1994), together with
evidence that transformed cells can be changed to a more
normal phenotype by syndecan-1 transfection (Leppä et al.,
1992), will turn attention to possibilities for regulating
syndecan expression (and cell behavior) at the gene level. This
type of approach is also encouraged by data showing that
growth factors are able to both induce (Elenius et al., 1992)
and suppress (Sneed et al., 1994; V. Kainulainen et al., unpublished data) syndecan-1 expression at the transcriptional level
in vitro, and indicates that new therapeutic strategies may
result from these studies.
Traditionally, heparan sulfate cell surface proteoglycans
have been called ‘low-affinity’ FGF receptors and the tyrosine
kinase-containing molecules ‘high-affinity’ FGF receptors,
respectively. It is, however, probable that the high-affinity
binding sites detected at cell surfaces have represented a
complex of a tyrosine kinase FGFR and a heparan sulfate proteoglycan instead of a tyrosine kinase FGFR alone (Nugent and
Edelman, 1992). In the light of new evidence, that tyrosine
kinase FGF receptors are unable to bind members of FGF
family without cooperation from heparan sulfate, the nomenclature should be changed. To avoid misunderstanding, the
terms ‘tyrosine kinase FGF receptor’ and ‘heparan sulfate FGF
co-receptor’ should be used. Similarly, the name co-receptor
would also be well suited to describing the action of cell
surface heparan sulfate proteoglycans (syndecans) as partners
of integrins in anchoring cells to the extracellular matrix. The
new knowledge indicates that specific structures of heparan
sulfate are needed for receptor and growth factor complex
formation (Guimond et al., 1993), as well as for interactions of
heparan sulfate with various matrix molecules (Salmivirta et
al., 1991). Therefore, structural studies of syndecan core
proteins, heparan sulfate and derived complexes with various
extracellular effector molecules should also be given a high
priority in the future. Information from these kinds of studies
would aid in the planning and synthesis of new molecules
mimicking these structures and, thus, would provide new pharmaceutical tools that would be useful in the treatment of
several pathological conditions, such as cancer and cardiovascular diseases.
The original work of Jalkanen group has been supported by the
Academy of Finland, the Finnish Cancer Institute, the Finnish Cancer
Union, the Farmos Research and Science Foundation and the Technology Development Centre of Finland. Fruitful discussions with
other members of Jalkanen group are greatly acknowledged.
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