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Curr Opin Cell Biol. Author manuscript; available in PMC 2010 October 1.
Published in final edited form as:
PMCID: PMC2758656
NIHMSID: NIHMS119911

The signalling mechanisms of syndecan heparan sulphate proteoglycans

Summary of recent advances

Syndecans are membrane proteins controlling cell proliferation, differentiation, adhesion and migration. Their extracellular domains bear versatile heparan sulphate chains that provide structural determinants for syndecans to function as co-receptors or activators for molecules like growth factors and constituents of the matrix. Syndecans also signal via their protein cores and their conserved transmembrane and cytoplasmic domains. The direct interactions and signalling cascades they support are becoming better characterized. These interactions are regulated by phosphorylation, induced clustering and shedding of the syndecan extracellular domain. Moreover evidence is emerging that syndecans concentrate in unconventional lipid domains and might govern novel vesicular trafficking pathways. Here we focus on recent findings that refine our understanding of the complex structure-function relationships of these cellular effectors.

Introduction

Syndecans are membrane proteins that are expressed at up to one million copies per cell in nearly every cell of the body. Mammals express four different syndecans. Each syndecan family member has a distinctive temporal and spatial pattern of expression. Syndecan-1 is primarily expressed in epithelial and plasma cells, syndecan-2 is mainly expressed in fibroblasts, endothelial cells, neurons and smooth muscle cells, syndecan-3 is the major syndecan of the nervous system but is also important for chondrocyte proliferation, and syndecan-4 is nearly ubiquitous.

In invertebrates like Drosophila melanogaster and C. elegans, there is only a single syndecan gene, which is essential for neuronal development and axon guidance. In mammals, knock-out animals are viable and fertile but show multiple defects following exposure to physiological stresses [1]. These include perturbed wound healing, angiogenesis and inflammation for syndecan-1-/- and -4-/-. Interestingly, syndecan-1 null mice are protected from tumour development possibly because of impaired pathogenic activation of progenitor/stem cells [2]. Syndecan-3 deficient mice have difficulties of learning and memory, develop muscular dystrophy and have an abnormal feeding behaviour after food deprivation [3]. To date, syndecan-2 null mice have not been reported, but studies in Xenopus and zebrafish point to a role in left-right asymmetry and VEGF induced vascular development [4]. In these same models, syndecan-4 is required for modulating migration processes during embryonic development that are regulated by the non-canonical Wnt pathway and for neural induction [5-7]. Xenopus syndecan-1 regulates dorso-ventral patterning of the ectoderm by modulating BMP signalling [8]. The severity of Xenopus/fish versus mice knock-out phenotypes may be because shorter gestational times are prohibitive of compensation mechanisms. The analysis of combined knock-outs should clarify how mammals accommodate the lack of multiple syndecans.

Structurally, all syndecans are composed of an extracellular domain (ED), a characteristic transmembrane region (TM) and a conserved short C-terminal cytoplasmic domain (CD). The ED is substituted with HS chains synthesized and modified in the Golgi-apparatus and edited post-synthetically by sulfatases and heparanase (Figure 1). The structural features of the HS chains are responsible for the interaction of syndecans with a number of soluble factors, cell-associated molecules and extracellular matrix components. In some cases HS engagement can promote the active conformation of the ligand. Generally, syndecans do not function as primary receptors but cooperate with these as co-receptors. Although in vitro experiments clearly indicated that specific HS-structures mediate specific high-affinity binding activities [9], loss-of-function studies of the different HS modifying enzymes in mice have established that compensation mechanisms can take place and that the ‘sugar code’ is quite degenerate [10-12]. Except for the HS attachment sites, the amino-acid sequence of the ED varies considerably between the different syndecan family members. Within a syndecan type there is usually over 70% homology between different mammals. A few studies now document that syndecan EDs contain non-HS intrinsic protein-binding structures such as the NXIP motif in syndecan-4 [13] and the ‘synstatin’ part of syndecan-1 that associates with alpha(v)beta(3) and alpha(v)beta(5) integrins and that can block angiogenesis and tumorigenesis [14]. The TM and CD domains harbour structural features that are unique to syndecans and support signal transduction across the membrane. Syndecans do not appear to encode any intrinsic catalytic activity, however multiple molecular interactions have been identified with kinases, GTPases, cytoskeletal molecules and other intracellular components (Table 1). These interactions are regulated by phosphorylation and clustering of the syndecans. Below we review how structural features of the TM and the CD of syndecans can contribute to their signalling, how heparanase and shedding can modulate their activity and how endocytic routes might support their function. Complementary information can be found in other recent reviews [1,15-17].

Figure 1
Syndecan structure
Table 1
Molecules directly interacting with syndecan transmembrane or cytoplasmic domain, and functional relevance thereof when established

Structure-function relationships in syndecans

A growing number of studies document the importance of a given syndecan in the activation of a particular signalling cascade, but these properties may be context or cell-type specific. In some cases, the syndecan ED (membrane anchored or soluble) has proven to suffice for supporting some aspects of their biological function, while other study-cases have demonstrated that the CD, or subdomains thereof, are essential or sometimes even sufficient, when clustered, to mediate biological effects. Ligand-induced clustering or multimerization of syndecans appears to be a key event during transmembrane signalling and is possibly linked to the property of syndecans to form detergent-resistant homo-multimers. Chimeric syndecan constructs in which the TM of syndecans is replaced by the TM of the PDGFR form very few detergent-resistant dimers and their specific signalling function is lost [18]. Multimerization requires the ubiquitously conserved GxxxG motif in the TM. Yet, the TM domains of the four different syndecans self-associate to very different degrees implicating residues outside the GxxxG motif in modulating the different associations [19]. Consistently, the minimal amino acid sequence that supports the ability of the syndecan-3 core protein to form multimeric complexes includes, in addition to the TM, the last four amino acids of the ED [20]. Although heteromeric interactions among full-length syndecans have not been reported in vivo, Dews and Mackenzie [19] recently showed that each syndecan TM is able to form stable heteromeric complexes with other paralogs. These interactions exhibit selectivity as, for example the TM of syndecan-1 forms a heterocomplex with syndecan-2 and syndecan-3 but not with syndecan-4. By extension, it would be interesting to know whether hetero-dimerization via the TM with non-syndecan receptors might support syndecan function as co-receptor.

The CD of the syndecans can be divided into two highly conserved regions (C1) and (C2) separated by a variable (V) region, unique for each syndecan (Figure 1). The importance of these domains was highlighted in studies using syndecan chimeras, deletion or point mutants and knock-out cells transfected with rescue constructs. The list of molecules directly interacting with the syndecan CD is growing and the functional relevance of these interactions has been clearly established in some cases (Table 1).

The identity of these interactions is significantly contributing to a progressive understanding of syndecan-specific signalling cascades such as the role of syndecan-2 in neuronal maturation. In neuronal cells, filopodia are recognized as one origin of dendritic spines, bulbous protrusions on the surface of dendrites which have been implicated as a cellular basis for learning and memory. In an elegant study, Lin et al. showed that neurofibromin, interacting with syndecan-2 C1, mediates the activation of PKA and consequent phosphorylation of Ena/VASP proteins that can then promote actin filament elongation by interacting with barbed ends [21]. This signalling cascade induces filopodia formation in cells and hippocampal neurons, but is not sufficient for the maturation of spines. In independent studies, Yamaguchi and co-workers showed that syndecan-2 clustering following tyrosine phosphorylation in the C1 and V region by EphB2 and the presence of the C2 domain are essential for the maturation of spines but not for filopodia formation [22,23]. These data demonstrate that syndecan-2 coordinates two sequential processes in neurons eventually resulting in the formation of dendritic spines.

Syndecan-4 has been the best characterized with respect to direct intracellular interactions of the CD (Table 1). Syndecan-4 localizes to cell attachment sites where together with the α5β1 integrin it generates stress fibers and focal adhesions [24] via activation of protein kinases (PKCalpha and Rho) and coordination of structural and adaptor proteins [16,25]. It has also been shown to transduce FGF-mediated signalling as part of a ternary complex via its protein core [17]. Although not completely defined, syndecan-4 has been shown to preferentially localize into lipid raft compartments following growth factor stimulation [17]. Redistribution of syndecan-4 to lipid rafts generates a potential means of controlling the initiation and duration of syndecan-4/FGF-2 signalling, as this complex is internalized in a Rac-dependent manner [17] and might be subsequently recycled to the cell surface via a syntenin-mediated mechanism (see below) [26]. Localization of syndecan-4 to the lamellipodium of migrating cells serves two purposes: to induce polarization by directing activated Rac to the leading edge [27,28] and to stimulate PKCalpha [29]. PKCalpha regulates cell spreading by activating Rho [30] while concurrently regulating that activation via targeted localization of phosphorylated p190RhoGAP [31]. Rho activation has also been shown to occur in a PKCalpha independent manner to promote phosphorylation of FAK tyrosine-397 leading to focal adhesion turnover [25]. This is in contrast to FGF-2 stimulation which diminishes FAK phosphorylation and leads to enhanced syndecan-4 mediated migration in M5 melanoma cells [32].

This divergence in outcome following syndecan-4 activation by either ECM or growth factor ligation, along with the selective localization of Rho and Rac, suggests that the proteoglycan serves to enact a balance between signalling pathways. In vivo studies, utilizing Xenopus and zebrafish models, have started to address this issue. Syndecan-4 mediated induction of parallel pathways (FGF/ERK and PKCalpha/Rac) promotes neural plate induction [5]. Syndecan-4 in complex with Frizzled 7 also supports the activation of the planar cell polarity (PCP) or non-canonical Wnt signalling pathway that is essential for appropriate directionality during convergence extension and neural crest cell (NC) migration, in response to adhesion to fibronectin [6,7]. Intriguingly, syntenin directly binds Frizzled 7 and syndecan-4 and also supports convergence extension [33] suggesting it might play a role in the formation or the activity of the complex, see also below.

Regulation of syndecan activity by heparanase and shedding

Heparanase cleaves HS-chains at a few specific sites producing fragments of 10-20 sugar units. HS-chain fragments generated by heparanase are biologically more active than the native HS-chain in FGF2 signalling. In addition and somewhat counter-intuitively, heparanase can transform syndecan into a highly selective interaction protein. Binding of lacritin, an epithelial proliferation factor, to the N-terminus of syndecan-1 is required for mitogenic signalling, but lacritin binding is only accomplished after partial or complete removal of the syndecan-1 HS-chains by heparanase [34]. Finally, heparanase does not only cleave HS-chains but is also able to induce syndecan-1 shedding and the functional consequence thereof (see below). Thus heparanase can modulate syndecan function in several ways.

Syndecan ED can be proteolytically cleaved in the juxtamembrane region, a process inducing the release of the ED called shedding (Figure 1). Proteolytic syndecan-1 cleavage is mediated by a variety of proteases of the matrix metalloproteinase (MMP) family. The MMPs involved are cell type specific yielding soluble proteoglycans (EDs) that in principle retain the binding properties of their cell surface precursors. All syndecan members are constitutively shed to some extent as part of their normal turn-over. Yet, shedding of the syndecan core proteins can be accelerated. A variety of extracellular stimuli like growth factors, chemokines, bacterial virulence factors and cell stress are known to induce syndecan-1 shedding. Recently heparanase has been shown to fine-tune the tumour micro-environment by controlling the shedding of syndecan-1. Knock-down of heparanase in myeloma cell lines results in a decrease of soluble syndecan-1 [35]. One possible mechanism to explain the effect of heparanase on syndecan shedding is that cleavage of the HS-chains by heparanase makes the syndecans more accessible for the proteases. How extracellular stimuli influence the sheddases to mediate syndecan cleavage is not yet clear. Chemical inhibitor studies suggest that diverse signal transduction cascades, such as protein kinase C, protein tyrosine kinase, mitogen-activated protein kinases and the nuclear factor kappaB pathways are involved. In addition, the CD seems to be essential for the regulation of agonist induced shedding. Hayashida et al. [36] showed that the CD of syndecan-1 binds to inactive Rab5 and dissociation is induced by agonist-mediated stimulation of shedding. Their data suggest that Rab-5 might serve as an intracellular on-off switch to control the onset of syndecan-1 shedding.

Release of syndecans from the cell surface by shedding clearly has functional consequences. Membrane-bound and soluble forms of syndecan-1 have opposite roles in breast carcinoma cells. Syndecan-1 overexpression stimulates proliferation of MCF-7 cells (adenocarcinoma), whereas overexpression of a constitutively shed syndecan-1 decreases the proliferation of these cells. Constitutively membrane-bound syndecan-1 inhibits invasiveness, whereas constitutively shed syndecan promotes invasion of these same cells [37]. Thus proteolytic conversion of syndecan-1 from a membrane-bound into a soluble molecule marks a switch from a proliferative to an invasive phenotype. Yet, the effect of the shed syndecan-1 ED on cell proliferation seems to be cell type specific, as exposure of the T47D human breast carcinoma cell line (ductal carcinoma) to shed syndecan-1 stimulates cell proliferation [38]. In Xenopus embryos, binding of FGF to syndecan-4 stimulates the shedding of syndecan-4 mediated by secreted serine protease xHtrA1. This releases soluble FGF-syndecan-4 complexes that serve as a long-range growth factor signalling complex for mesoderm induction and body plan establishment [39]. Finally it has been shown that, upon shedding of the ED, the remaining C-terminal fragment is further fragmented by presenilins (Figure 1). Such intramembrane proteolysis might be a mechanism for terminating signal transduction across the membrane and/or for sending soluble signals in the cytosol [40].

Endocytic routes and syndecan function

HSPGs and syndecans are not only essential for the internalization of physiological extracellular ligands, but also for that of viruses, bacteria and basic peptides or poly-cation-nucleic-acid complexes [41-43]. The early endocytic routes used by syndecans appear unconventional and characteristic (Figure 2) [17,44-52]. After clustering, syndecans are internalized by clathrin- and caveolin-independent routes. Several observations point to a role for membrane rafts and macropinocytosis. Requirement of dynamin, flotilin-1 or Rac activation might be context-dependent (i. e. cell-specific syndecan expression, nature of the ligand, presence of co-receptors and/or cell-type specific machineries). An intriguing observation is that dynamin interacts with syndecan-4 C1 region [53] suggesting syndecans might be mechanistically linked to endosome formation. Our knowledge of the fate of the syndecans after internalization is quite limited. Some traffic through late endosomes [49] and then to lysosomes to be degraded together with their cargo, which would support syndecan-dependent signal extinction. Interestingly the C2 domain, not important for syndecan internalization per se [26], supports alternative endocytic routes. This domain corresponds to a canonical PDZ-binding motif (PDZBM). PDZ interactions are important for cell polarization and support the targeting and organization of large signalling complexes. Syntenin was the first PDZ protein identified to bind the C2 domain of the syndecans. It functions as a rate limiting factor for syndecan plasma membrane recycling and likely for the recycling of HS associated cargo like FGF/FGFR. Mechanistically, this pathway relies on the ability of syntenin PDZ domains to interact with PIP2 and on the activation of ARF6 GTPase on perinuclear endosomes [26]. Intriguingly, another role for syntenin might be to support syndecan-dependent [7] non-canonical Wnt signalling (see above). Indeed syntenin directly interacts with Frizzled, Wnt receptors and can bridge them to syndecan. Moreover syntenin is necessary for convergent-extension movements and mediates PKCalpha membrane recruitment [33]. How this might be supported by syndecan-syntenin recycling has not been investigated. A second PDZ protein, the relevance of which has been more specifically established in the context of syndecan-4 biology, is synectin/GIPC. Synectin appears important for syndecan-4 dependant activation of Rac at the leading edge and thereby for syndecan-4 dependant endothelial cell migration [28]. It is worth noting that the mechanisms supporting synectin function might involve actin-dependent endocytic trafficking [54]. Synbindin, a third protein that interacts with the PDZBM of syndecan-2, is involved in membrane trafficking at post-synaptic sites and might support the maturation of dendritic spines that depend on syndecan-2 and their PDZBM (see also above) [55]. Finally, the PDZBM of syndecan-1 was shown to mediate polarized secretion to the basolateral membrane of epithelial cells [56]. None of the known PDZ interactors of syndecan PDZBM (Table 1) can account for this effect indicating that other PDZ proteins relevant for syndecan biology remain to be discovered.

Figure 2
Syndecan intracellular trafficking

In summary, syndecans might represent specific ‘trafficking machines’ for cargo to be secreted, degraded or reutilized. This function is influenced by their clustering and also depends on the interaction of their C2 domain with different PDZ proteins.

Concluding remarks

Syndecans have complex structure-function relationships. By means of their versatile HS chains they sense extracellular environments. As co-receptors for cell-adhesion, cell-proliferation and fate determination molecules and other extracellular signals, they collaborate with ‘primary’ receptors to control signalling. Their conserved TM and CD add specificity to their signalling, by supporting oligomerization and various intracellular connections in a regulated manner. Relatively little is known about the mechanisms by which extra and intracellular domain functions are integrated or disconnected by shedding. When does the CD function in concert with the ED, and does it function after ED cleavage? Does repulsion due to HS negative charges compromise self-assembly required for signalling? The investigation of syndecan endocytic routes has been neglected but emerging studies point to requisite and unanticipated functions in the control of signalling. Our knowledge of these mechanisms is still scarce. Yet, discovering the intricate and subtle dynamics of syndecan signalling might provide opportunities for the treatment of cancer, wound healing, inflammation, viral and bacterial pathogenesis as well as contribute greatly to stem cell biology and cell therapy.

Acknowledgments

We apologize to colleagues whose work we could not describe owing to the condensed format. We thank Prof. Guido David for his feedback during the redaction of the manuscript and Prof. Bassem Hassan and Dr. Aurélie Melchior for their suggestions and proofreading. The laboratory of PZ is supported by the Fund for Scientific Research-Flanders (FWO), the Interuniversity Attraction Poles of the Prime Ministers Services (IUAP), the Belgian Federation against Cancer (BFK), the Concerted Actions Program of the K.U.Leuven and the EMBO young investigator program.

Footnotes

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References

1. Alexopoulou AN, Multhaupt HA, Couchman JR. Syndecans in wound healing, inflammation and vascular biology. Int J Biochem Cell Biol. 2007;39:505–528. [PubMed]
2. McDermott SP, Ranheim EA, Leatherberry VS, Khwaja SS, Klos KS, Alexander CM. Juvenile syndecan-1 null mice are protected from carcinogen-induced tumor development. Oncogene. 2007;26:1407–1416. [PubMed]
3. Reizes O, Benoit SC, Clegg DJ. The role of syndecans in the regulation of body weight and synaptic plasticity. Int J Biochem Cell Biol. 2008;40:28–45. [PubMed]
4. Essner JJ, Chen E, Ekker SC. Syndecan-2. Int J Biochem Cell Biol. 2006;38:152–156. [PubMed]
• 5. Kuriyama S, Mayor R. A role for Syndecan-4 in neural induction involving ERK- and PKC-dependent pathways. Development. 2009;136:575–584. [PubMed]This study demonstrates that the PKCalpha/Rho pathway implicated in syndecan-4 mediated cell migration is also important in neuronal cell specification.
6. Matthews HK, Marchant L, Carmona-Fontaine C, Kuriyama S, Larrain J, Holt MR, Parsons M, Mayor R. Directional migration of neural crest cells in vivo is regulated by Syndecan-4/Rac1 and non-canonical Wnt signaling/RhoA. Development. 2008;135:1771–1780. [PubMed]
• 7. Munoz R, Moreno M, Oliva C, Orbenes C, Larrain J. Syndecan-4 regulates non-canonical Wnt signalling and is essential for convergent and extension movements in Xenopus embryos. Nat Cell Biol. 2006;8:492–500. [PubMed]This paper shows that syndecan-4 ligation of fibronectin results in the translocation of Dishevelled to the plasma membrane and that syndecan-4 cooperates with Frizzled 7 to activate non-canonical Wnt signalling in Xenopus.
8. Olivares GH, Carrasco H, Aroca F, Carvallo L, Segovia F, Larrain J. Syndecan-1 regulates BMP signaling and dorso-ventral patterning of the ectoderm during early Xenopus development. Dev Biol. 2009 [PubMed]
9. Mahalingam Y, Gallagher JT, Couchman JR. Cellular adhesion responses to the heparin-binding (HepII) domain of fibronectin require heparan sulfate with specific properties. J Biol Chem. 2007;282:3221–3230. [PubMed]
10. Bishop JR, Schuksz M, Esko JD. Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature. 2007;446:1030–1037. [PubMed]
11. Kreuger J, Spillmann D, Li JP, Lindahl U. Interactions between heparan sulfate and proteins: the concept of specificity. J Cell Biol. 2006;174:323–327. [PMC free article] [PubMed]
12. Lamanna WC, Kalus I, Padva M, Baldwin RJ, Merry CL, Dierks T. The heparanome--the enigma of encoding and decoding heparan sulfate sulfation. J Biotechnol. 2007;129:290–307. [PubMed]
13. Whiteford JR, Couchman JR. A conserved NXIP motif is required for cell adhesion properties of the syndecan-4 ectodomain. J Biol Chem. 2006;281:32156–32163. [PubMed]
• • 14. Beauvais DM, Ell BJ, McWhorter AR, Rapraeger AC. Syndecan-1 regulates alphavbeta3 and alphavbeta5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor. J Exp Med. 2009;206:691–705. [PMC free article] [PubMed]This research demonstrates that the extracellular domain of syndecan-1 directly interacts with and activates the alpha(v)beta(3) and alpha(v)beta(5) integrins to promote angiogenesis.
15. Couchman JR. Syndecans: proteoglycan regulators of cell-surface microdomains? Nat Rev Mol Cell Biol. 2003;4:926–937. [PubMed]
16. Morgan MR, Humphries MJ, Bass MD. Synergistic control of cell adhesion by integrins and syndecans. Nat Rev Mol Cell Biol. 2007;8:957–969. [PMC free article] [PubMed]
17. Tkachenko E, Rhodes JM, Simons M. Syndecans: new kids on the signaling block. Circ Res. 2005;96:488–500. [PubMed]
18. Choi S, Lee E, Kwon S, Park H, Yi JY, Kim S, Han IO, Yun Y, Oh ES. Transmembrane domain-induced oligomerization is crucial for the functions of syndecan-2 and syndecan-4. J Biol Chem. 2005;280:42573–42579. [PubMed]
19. Dews IC, Mackenzie KR. Transmembrane domains of the syndecan family of growth factor coreceptors display a hierarchy of homotypic and heterotypic interactions. Proc Natl Acad Sci U S A. 2007;104:20782–20787. [PubMed]
20. Asundi VK, Carey DJ. Self-association of N-syndecan (syndecan-3) core protein is mediated by a novel structural motif in the transmembrane domain and ectodomain flanking region. J Biol Chem. 1995;270:26404–26410. [PubMed]
• • 21. Lin YL, Lei YT, Hong CJ, Hsueh YP. Syndecan-2 induces filopodia and dendritic spine formation via the neurofibromin-PKA-Ena/VASP pathway. J Cell Biol. 2007;177:829–841. [PMC free article] [PubMed]This study reveals a novel signalling pathway in which syndecan-2 by directly interacting with neurofibromin activates PKA that consequently phosphorylates Ena/VASP, promoting filopodia formation.
22. Ethell IM, Irie F, Kalo MS, Couchman JR, Pasquale EB, Yamaguchi Y. EphB/syndecan-2 signaling in dendritic spine morphogenesis. Neuron. 2001;31:1001–1013. [PubMed]
23. Ethell IM, Yamaguchi Y. Cell surface heparan sulfate proteoglycan syndecan-2 induces the maturation of dendritic spines in rat hippocampal neurons. J Cell Biol. 1999;144:575–586. [PMC free article] [PubMed]
24. Woods A, Couchman JR. Syndecan-4 and focal adhesion function. Curr Opin Cell Biol. 2001;13:578–583. [PubMed]
25. Wilcox-Adelman SA, Denhez F, Iwabuchi T, Saoncella S, Calautti E, Goetinck PF. Syndecan-4: dispensable or indispensable? Glycoconj J. 2002;19:305–313. [PubMed]
• • 26. Zimmermann P, Zhang Z, Degeest G, Mortier E, Leenaerts I, Coomans C, Schulz J, N'Kuli F, Courtoy PJ, David G. Syndecan recycling [corrected] is controlled by syntenin-PIP2 interaction and Arf6. Dev Cell. 2005;9:377–388. [PubMed]The first study identifying the mechanism of syndecan endocytic recycling and showing it is supported by its interaction with the PDZ protein syntenin.
• • 27. Bass MD, Roach KA, Morgan MR, Mostafavi-Pour Z, Schoen T, Muramatsu T, Mayer U, Ballestrem C, Spatz JP, Humphries MJ. Syndecan-4-dependent Rac1 regulation determines directional migration in response to the extracellular matrix. J Cell Biol. 2007;177:527–538. [PMC free article] [PubMed]Demonstration of the role of syndecan-4 in mediating directionally persistent migration by localizing active Rac1, in response to the ECM.
28. Tkachenko E, Elfenbein A, Tirziu D, Simons M. Syndecan-4 clustering induces cell migration in a PDZ-dependent manner. Circ Res. 2006;98:1398–1404. [PubMed]
29. Keum E, Kim Y, Kim J, Kwon S, Lim Y, Han I, Oh ES. Syndecan-4 regulates localization, activity and stability of protein kinase C-alpha. Biochem J. 2004;378:1007–1014. [PubMed]
30. Dovas A, Yoneda A, Couchman JR. PKCalpha-dependent activation of RhoA by syndecan-4 during focal adhesion formation. J Cell Sci. 2006;119:2837–2846. [PubMed]
• 31. Bass MD, Morgan MR, Roach KA, Settleman J, Goryachev AB, Humphries MJ. p190RhoGAP is the convergence point of adhesion signals from alpha 5 beta 1 integrin and syndecan-4. J Cell Biol. 2008;181:1013–1026. [PMC free article] [PubMed]This study demonstrates the role of syndcan-4 in regulating Rho activation at the leading edge by inducing the redistribution of p190RhoGAP between the membrane and the cytosol.
32. Chalkiadaki G, Nikitovic D, Berdiaki A, Sifaki M, Krasagakis K, Katonis P, Karamanos NK, Tzanakakis GN. Fibroblast growth factor-2 modulates melanoma adhesion and migration through a syndecan-4-dependent mechanism. Int J Biochem Cell Biol. 2009;41:1323–1331. [PubMed]
33. Luyten A, Mortier E, Van Campenhout C, Taelman V, Degeest G, Wuytens G, Lambaerts K, David G, Bellefroid EJ, Zimmermann P. The postsynaptic density 95/disc-large/zona occludens protein syntenin directly interacts with frizzled 7 and supports noncanonical Wnt signaling. Mol Biol Cell. 2008;19:1594–1604. [PMC free article] [PubMed]
• • 34. Ma P, Beck SL, Raab RW, McKown RL, Coffman GL, Utani A, Chirico WJ, Rapraeger AC, Laurie GW. Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin. J Cell Biol. 2006;174:1097–1106. [PMC free article] [PubMed]This study shows that the modification of the syndecan HS chains by heparanase works as an ‘off-on’ switch for the interaction between lacritin and syndecan-1.
35. Mahtouk K, Hose D, Raynaud P, Hundemer M, Jourdan M, Jourdan E, Pantesco V, Baudard M, De Vos J, Larroque M, et al. Heparanase influences expression and shedding of syndecan-1, and its expression by the bone marrow environment is a bad prognostic factor in multiple myeloma. Blood. 2007;109:4914–4923. [PMC free article] [PubMed]
• 36. Hayashida K, Stahl PD, Park PW. Syndecan-1 ectodomain shedding is regulated by the small GTPase Rab5. J Biol Chem. 2008;283:35435–35444. [PMC free article] [PubMed]This study shows that the association of Rab5 with syndecan-1 cytoplasmic domain controls shedding and that the dissociation of the complex is agonist induced.
37. Nikolova V, Koo CY, Ibrahim SA, Wang Z, Spillmann D, Dreier R, Kelsch R, Fischgrabe J, Smollich M, Rossi LH, et al. Differential roles for membrane-bound and soluble syndecan-1 (CD138) in breast cancer progression. Carcinogenesis. 2009;30:397–407. [PubMed]
38. Su G, Blaine SA, Qiao D, Friedl A. Shedding of syndecan-1 by stromal fibroblasts stimulates human breast cancer cell proliferation via FGF2 activation. J Biol Chem. 2007;282:14906–14915. [PubMed]
• 39. Hou S, Maccarana M, Min TH, Strate I, Pera EM. The secreted serine protease xHtrA1 stimulates long-range FGF signaling in the early Xenopus embryo. Dev Cell. 2007;13:226–241. [PubMed]This paper shows that, in Xenopus embryos, binding of FGF to syndecan-4 stimulates the secreted serine protease xHtrA1 mediated shedding of syndecan-4 and that these soluble FGF-syndecan-4 complexes act as a long range signalling complex.
40. Schulz JG, Annaert W, Vandekerckhove J, Zimmermann P, De Strooper B, David G. Syndecan 3 intramembrane proteolysis is presenilin/gamma-secretase-dependent and modulates cytosolic signaling. J Biol Chem. 2003;278:48651–48657. [PubMed]
41. Belting M. Heparan sulfate proteoglycan as a plasma membrane carrier. Trends Biochem Sci. 2003;28:145–151. [PubMed]
42. Gallay P. Syndecans and HIV-1 pathogenesis. Microbes Infect. 2004;6:617–622. [PubMed]
43. Smith MF, Jr, Gautam JK, Black SG, Ernst PB. Microbial-induced regulation of syndecan expression: important host defense mechanism or an opportunity for pathogens? ScientificWorldJournal. 2006;6:442–445. [PubMed]
44. Fan TC, Chang HT, Chen IW, Wang HY, Chang MD. A heparan sulfate-facilitated and raft-dependent macropinocytosis of eosinophil cationic protein. Traffic. 2007;8:1778–1795. [PubMed]
45. Fuki IV, Kuhn KM, Lomazov IR, Rothman VL, Tuszynski GP, Iozzo RV, Swenson TL, Fisher EA, Williams KJ. The syndecan family of proteoglycans. Novel receptors mediating internalization of atherogenic lipoproteins in vitro. J Clin Invest. 1997;100:1611–1622. [PMC free article] [PubMed]
46. Fuki IV, Meyer ME, Williams KJ. Transmembrane and cytoplasmic domains of syndecan mediate a multi-step endocytic pathway involving detergent-insoluble membrane rafts. Biochem J. 2000;351(Pt 3):607–612. [PubMed]
47. Nakase I, Tadokoro A, Kawabata N, Takeuchi T, Katoh H, Hiramoto K, Negishi M, Nomizu M, Sugiura Y, Futaki S. Interaction of arginine-rich peptides with membrane-associated proteoglycans is crucial for induction of actin organization and macropinocytosis. Biochemistry. 2007;46:492–501. [PubMed]
48. Nishi K, Saigo K. Cellular internalization of green fluorescent protein fused with herpes simplex virus protein VP22 via a lipid raft-mediated endocytic pathway independent of caveolae and Rho family GTPases but dependent on dynamin and Arf6. J Biol Chem. 2007;282:27503–27517. [PubMed]
49. Payne CK, Jones SA, Chen C, Zhuang X. Internalization and trafficking of cell surface proteoglycans and proteoglycan-binding ligands. Traffic. 2007;8:389–401. [PMC free article] [PubMed]
50. Tkachenko E, Simons M. Clustering induces redistribution of syndecan-4 core protein into raft membrane domains. J Biol Chem. 2002;277:19946–19951. [PubMed]
51. Wilsie LC, Gonzales AM, Orlando RA. Syndecan-1 mediates internalization of apoE-VLDL through a low density lipoprotein receptor-related protein (LRP)-independent, non-clathrin-mediated pathway. Lipids Health Dis. 2006;5:23. [PMC free article] [PubMed]
52. Wittrup A, Sandgren S, Lilja J, Bratt C, Gustavsson N, Morgelin M, Belting M. Identification of proteins released by mammalian cells that mediate DNA internalization through proteoglycan-dependent macropinocytosis. J Biol Chem. 2007;282:27897–27904. [PubMed]
53. Yoo J, Jeong MJ, Cho HJ, Oh ES, Han MY. Dynamin II interacts with syndecan-4, a regulator of focal adhesion and stress-fiber formation. Biochem Biophys Res Commun. 2005;328:424–431. [PubMed]
54. Naccache SN, Hasson T, Horowitz A. Binding of internalized receptors to the PDZ domain of GIPC/synectin recruits myosin VI to endocytic vesicles. Proc Natl Acad Sci U S A. 2006;103:12735–12740. [PubMed]
55. Ethell IM, Hagihara K, Miura Y, Irie F, Yamaguchi Y. Synbindin, A novel syndecan-2-binding protein in neuronal dendritic spines. J Cell Biol. 2000;151:53–68. [PMC free article] [PubMed]
56. Maday S, Anderson E, Chang HC, Shorter J, Satoh A, Sfakianos J, Folsch H, Anderson JM, Walther Z, Mellman I. A PDZ-binding motif controls basolateral targeting of syndecan-1 along the biosynthetic pathway in polarized epithelial cells. Traffic. 2008;9:1915–1924. [PMC free article] [PubMed]
57. Paris S, Burlacu A, Durocher Y. Opposing roles of syndecan-1 and syndecan-2 in polyethyleneimine-mediated gene delivery. J Biol Chem. 2008;283:7697–7704. [PubMed]