1 Nature Reviews Molecular Cell Biology 2003 Vol: 4(12):926-938. DOI: 10.1038/nrm1257

Syndecans: proteoglycan regulators of cell-surface microdomains?

Syndecans function as membrane receptors for a bewildering array of ligands through their glycosaminoglycan chains but their precise roles have been hard to pin down. Syndecans have previously been considered as ligand gatherers, working as co-receptors in collaboration with signalling receptors, but their potential to signal independently is now clear. New structural features of syndecan cytoplasmic domains have been described, together with new insights into signalling across the cell membrane that might involve the concentration of ligands in membrane microdomains.

Mentions
Figures
Figure 1: Syndecan core-domain structure and potential interactions.A schematic view of a syndecan, showing the core protein and glycosaminoglycan chains. Potential interactions, where known, are indicated. CS, chondroitin sulphate; ECTO, ectodomain; HS, heparan sulphate; TM, transmembrane domain; C1 and C2 refer to conserved regions 1 and 2, and V refers to the variable region, of the cytoplasmic domain. Figure 2: Syndecan-4 cytoplasmic domain and its interaction with PtdIns(4,5)P2.Models were generated from data obtained by nuclear-magnetic-resonance spectroscopy. On the left is a free dimer, whereas on the right, a complex of a dimer with a molecule of phosphatidylinositol-(4,5)-bisphosphate (PtdIns(4,5)P2) is shown. The figures show the surface electrostatic potential of the syndecan-4 cytoplasmic domain. Negative electrostatic potential is represented in red, positive in blue and neutral in white. The potential surface was calculated using the Delphi programme (Biosym/Molecular Simulation Inc.). The central V-region dimer (from L186 to K193) interacts with an inositol phospholipid molecule, indicating that this part of syndecan 4 is closely apposed to the inner face of the plasma membrane. Figure provided courtesy of Dr. W. Lee, Yonsei University, Seoul, Korea. Figure 3: Phosphorylation of syndecan 2.A schematic diagram of syndecan 2 that shows, in its cytoplasmic domain, two tyrosine residues on either side of the variable (V) region that can be phosphorylated by EphB2 kinase and that are involved in dendritic-spine maturation (see text for further details). Two serine residues in the V region can be phosphorylated by protein kinase C and are involved in determining left–right asymmetry in Xenopus development (see text for further details). C1 and C2 refer to conserved regions 1 and 2 of the cytoplasmic domain; ECTO, ectodomain; HS, heparan sulphate; TM, transmembrane domain. Figure 4: Syndecan 2, EphB2 receptors and dendritic-spine maturation.A diagram of a dendritic spine is shown, with some of the known components and interactions. Spine maturation is promoted by ectopic expression of syndecan 2 and involves the actin cytoskeleton, which is regulated by the GTPase Cdc42. Syndecan 2 is tyrosine phosphorylated by the EphB2 receptor tyrosine kinase, which might lead to clustering and cytoplasmic interaction with the PDZ (PSD95 (postsynaptic-density protein of 95kDa), Discs large, Zona occludens 1) protein CASK (calcium/calmodulin-dependent serine protein kinase), and the related protein synbindin. CASK has been shown to interact with actin-associated proteins, but whether there are additional direct interactions of syndecan 2 with the cytoskeleton is unknown. EphB2 receptors can also associate with N-methyl-d-aspartate (NMDA) receptors (NMDARs) that are linked to the alternative PDZ protein PSD95. Linkage of PSD95 to the cytoskeleton might be mediated by spine-associated Rap (SPAR), a GTPase activating protein. Although dendritic spines are actin-rich structures, microtubules are excluded. Drebrin, kalirin-7, spinophilin and cortactin are spine morphogens, of which the last two interact directly with actin. The others interact indirectly. AMPAR, -amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor. Figure 5: Left–right asymmetery in Xenopus.The cytoplasmic domain of syndecan 2 is phosphorylated by protein kinase C (PKC) in right-side ectoderm, but not in left-side ectoderm. PKC and syndecan 2 are required for left–right development during gastrulation, concurrent with the migration of mesoderm along the ectoderm. Left–right information is transmitted from ECTODERM to mesoderm, probably by the interaction of ectodermal syndecan 2 with the transforming-growth-factor- signalling pathway in mesoderm. Diagram courtesy of Drs. K. L. Kramer and H. J. Yost, University of Utah. Figure 6: A ternary complex of PtdIns(4,5)P2, syndecan 4 and protein kinase C.The complex, which comprises phosphatidylinositol-(4,5)-bisphosphate (Ptd(4,5)P2), two dimers of the syndecan-4 cytoplasmic domain and protein kinase C (PKC), might phosphorylate regulators of Rho-family GTPases and actin-associated proteins, leading to activation of Rho kinases (ROCKs). Downstream substrates include myosin light chain and myosin light-chain phosphatase, which lead to myosin-driven contraction, and the formation of microfilament bundles and focal adhesions. The syndecan-4 cytoplasmic domain is subject to phosphorylation by PKC, which strongly reduces its affinity for inositol phospholipid. A marked decrease in PKC binding and activity results. Dia, diaphanous.
Altmetric
References
  1. Selleck, S. B. Proteoglycans and pattern formation. Sugar biochemistry meets developmental genetics. Trends Genet. 16, 206-212 , (2000) .
    • . . . As with EXTRACELLULAR MATRIX (ECM) molecules and adhesion receptors, proteoglycan diversity increased greatly with the evolution of vertebrates, and some proteoglycans are essential for the development and function of the vertebrate skeleton, immune system and central nervous system1, 2. . . .
  2. Perrimon, N. & Bernfield, M. Specificities of heparan sulphate proteoglycans in developmental processes. Nature 404, 725-728 , (2000) .
    • . . . As with EXTRACELLULAR MATRIX (ECM) molecules and adhesion receptors, proteoglycan diversity increased greatly with the evolution of vertebrates, and some proteoglycans are essential for the development and function of the vertebrate skeleton, immune system and central nervous system1, 2. . . .
  3. Park, P. W., Reizes, O. & Bernfield, M. Cell surface heparan sulfate proteoglycans: selective regulators of ligand-receptor encounters. J. Biol. Chem. 275, 29923-29926 , (2000) .
    • . . . Membrane-associated proteoglycans are mostly heparan-sulphate substituted (Box 1) and can either be transmembrane or GLYCOSYLPHOSPHATIDYLINOSITOL (GPI)-ANCHORED3, 4 . . .
  4. Filmus, J. Glypicans in growth and cancer. Glycobiology 11, 19R-23R , (2001) .
    • . . . Membrane-associated proteoglycans are mostly heparan-sulphate substituted (Box 1) and can either be transmembrane or GLYCOSYLPHOSPHATIDYLINOSITOL (GPI)-ANCHORED3, 4 . . .
    • . . . In vivo data indicate that each syndecan is present at specific times in development, and on specific cell types4, 9 . . .
  5. Bernfield, M. et al. Functions of cell surface heparan sulfate proteoglycans. Annu. Rev. Biochem. 68, 729-777 , (1999) .
    • . . . There are four syndecans in mammals and probably in all vertebrates, whereas, in all invertebrates studied so far, there is just one5, 6, 7 . . .
    • . . . Three further mammalian members of the family were later cloned, accompanied by one each in Drosophila melanogaster, Caenorhabditis elegans, Ciona and Anthocidaris5, 7 . . .
    • . . . Very early on it was suggested that such molecules could function as 'receptors' for ECM glycoproteins, even though little was understood beyond a participation of heparan sulphate in the process5 . . .
    • . . . On the basis of protein sequence homology, vertebrate syndecan 1 and syndecan 3 form one subfamily, whereas syndecan 2 and syndecan 4 make up the other5, 7 . . .
    • . . . Sometimes syndecan 1 and syndecan 3 might also bear chondroitin or dermatan sulphate5(Fig. 1) . . .
    • . . . The extracellular domains have low homology with each other, except around the areas of glycosaminoglycan substitution5, 7 . . .
    • . . . This led to the idea that syndecans are, in an evolutionary sense, rapidly diverging, and that the ectodomains have little function other than to bear the glycosaminoglycan chains that interact with protein ligands5 (Box 2) . . .
    • . . . Cadherins associate with the actin cytoskeleton but, although there is much circumstantial support that this provides the link to syndecans5, 14, 26, 27, no direct interactions between syndecan 1 and cytoskeletal proteins have been reported. . . .
    • . . . Tyrosine residues in the syndecan cytoplasmic domains are highly conserved5, 7, 14, but so far, no Src-homology-2 (SH2)-domain-containing proteins have been shown to bind as a consequence of tyrosine phosphorylation . . .
  6. Rapraeger, A. C. Molecular interactions of syndecans during development. Semin. Cell Dev. Biol. 12, 107-116 , (2001) .
    • . . . There are four syndecans in mammals and probably in all vertebrates, whereas, in all invertebrates studied so far, there is just one5, 6, 7 . . .
  7. Couchman, J. R., Chen, L. & Woods, A. Syndecans and cell adhesion. Int. Rev. Cytol. 207, 113-150 , (2001) .
    • . . . There are four syndecans in mammals and probably in all vertebrates, whereas, in all invertebrates studied so far, there is just one5, 6, 7 . . .
    • . . . Three further mammalian members of the family were later cloned, accompanied by one each in Drosophila melanogaster, Caenorhabditis elegans, Ciona and Anthocidaris5, 7 . . .
    • . . . On the basis of protein sequence homology, vertebrate syndecan 1 and syndecan 3 form one subfamily, whereas syndecan 2 and syndecan 4 make up the other5, 7 . . .
    • . . . The cytoplasmic domains have been divided, for convenience, into three regions7 . . .
    • . . . However, the variability refers to comparisons of the family members; within one syndecan — for example amphibian, avian and mammalian syndecan 2 — the V region is absolutely conserved7 . . .
    • . . . Indeed, such is their affinity that purified and recombinant syndecan core proteins resolve as dimers using SDS-PAGE7, 14 . . .
    • . . . Furthermore, the ectodomains and cytoplasmic domains can also form dimers7, 15 . . .
    • . . . Tyrosine residues in the syndecan cytoplasmic domains are highly conserved5, 7, 14, but so far, no Src-homology-2 (SH2)-domain-containing proteins have been shown to bind as a consequence of tyrosine phosphorylation . . .
    • . . . This process also occurs in other cell types7, 50 . . .
    • . . . One advantage is that it is present in the focal adhesions of several cell types7, 50, 57, 58 . . .
    • . . . The V region of syndecan 4 is certainly very unlike that of any other family member, invertebrates included7 . . .
    • . . . At present, therefore, it is suspected that syndecan 4, PKC and the phospholipid form a ternary signalling complex that is localized to the nascent focal adhesions7, 50, 67, 68 (Fig. 6) . . .
  8. Saunders, S., Jalkanen, M., O'Farrell, S. & Bernfield, M. Molecular cloning of syndecan, an integral membrane proteoglycan. J. Cell Biol. 108, 1547-1556 , (1989) .
    • . . . The first mammalian member of the family, which is now known as syndecan 1, was cloned after several biochemical and cell biological experiments identified heparan-sulphate proteoglycans with hydrophobic properties on the surface of various cell types8 . . .
  9. Bernfield, M. et al. Biology of the syndecans: a family of transmembrane heparan sulfate proteoglycans. Annu. Rev. Cell Biol. 8, 365-393 , (1992) .
    • . . . In vivo data indicate that each syndecan is present at specific times in development, and on specific cell types4, 9 . . .
    • . . . Not surprisingly, this led to studies of syndecans in tumorigenesis and development, in which EPITHELIAL–MESENCHYMAL TRANSITIONS occur9 . . .
  10. David, G., Van der Schueren, B., Marynen, P., Cassiman, J. -J. & Van den Berghe, H. Molecular cloning of amphiglycan, a novel integral membrane heparan sulfate proteoglycan expressed by epithelial and fibroblastic cells. J. Cell Biol. 118, 961-969 , (1992) .
    • . . . Syndecan 4 is the 'odd one out' in some ways, being widely distributed in development and present in many different cell types10 . . .
  11. McFall, A. J. & Rapraeger, A. C. Identification of an adhesion site within the syndecan-4 extracellular protein domain. J. Biol. Chem. 272, 12901-12904 , (1997) .
    • . . . However, this could be an oversimplification, as reports on syndecan 1 and syndecan 4 indicate that some protein–protein interactions involve ectodomain regions11, 12, 13 . . .
    • . . . The ectodomains of syndecans have not received sufficient attention given that there are suggestions of biological function beyond bearing the glycosaminoglycan chains11, 12 . . .
  12. McFall, A. J. & Rapraeger, A. C. Characterization of the high affinity cell-binding domain in the cell surface proteoglycan syndecan-4. J. Biol. Chem. 273, 28270-28276 , (1998) .
    • . . . However, this could be an oversimplification, as reports on syndecan 1 and syndecan 4 indicate that some protein–protein interactions involve ectodomain regions11, 12, 13 . . .
    • . . . The ectodomains of syndecans have not received sufficient attention given that there are suggestions of biological function beyond bearing the glycosaminoglycan chains11, 12 . . .
    • . . . Moreover, adhesion to the mouse syndecan-4 ectodomain could be blocked by the chicken homologue12, even though — in terms of primary sequence — avian and mammalian ectodomains are not highly conserved . . .
  13. Liu, W. et al. Heparan sulfate proteoglycans as adhesive and anti-invasive molecules. Syndecans and glypican have distinct functions. J. Biol. Chem. 273, 22825-22832 , (1998) .
    • . . . However, this could be an oversimplification, as reports on syndecan 1 and syndecan 4 indicate that some protein–protein interactions involve ectodomain regions11, 12, 13 . . .
    • . . . Data from lymphoblastoid cells, this time examining syndecan 1, led to similar conclusions13 . . .
  14. Carey, D. J. Syndecans: multifunctional cell-surface co-receptors. Biochem. J. 327, 1-16 , (1997) .
    • . . . Each syndecan has an unusual transmembrane domain in which the sequences that are predicted to localize to the OUTER PLASMA-MEMBRANE LEAFLET are glycine-rich; there is also a more usual sequence that is rich in hydrophobic residues for the INNER LEAFLET14 . . .
    • . . . Indeed, such is their affinity that purified and recombinant syndecan core proteins resolve as dimers using SDS-PAGE7, 14 . . .
    • . . . Cadherins associate with the actin cytoskeleton but, although there is much circumstantial support that this provides the link to syndecans5, 14, 26, 27, no direct interactions between syndecan 1 and cytoskeletal proteins have been reported. . . .
    • . . . Tyrosine residues in the syndecan cytoplasmic domains are highly conserved5, 7, 14, but so far, no Src-homology-2 (SH2)-domain-containing proteins have been shown to bind as a consequence of tyrosine phosphorylation . . .
    • . . . So, is syndecan 4 the only one to have the twisted-clamp motif in its cytoplasmic domain that interacts with the membrane? All syndecans probably have dimeric cytoplasmic domains, especially as the adjacent transmembrane domains have such a high self-association tendency14, bringing the cytoplasmic domains into proximity . . .
  15. Oh, E. -S., Woods, A. & Couchman, J. R. Multimerization of the cytoplasmic domain of syndecan-4 is required for its ability to activate protein kinase C. J. Biol. Chem. 272, 11805-11811 , (1997) .
    • . . . Furthermore, the ectodomains and cytoplasmic domains can also form dimers7, 15 . . .
    • . . . Evidence indicates that the lipid binds this motif and stabilizes the syndecan-4 cytoplasmic domain in a dimeric form15, 16 (Fig. 2) . . .
    • . . . Quite possibly, it might also promote higher-order oligomers15 . . .
  16. Lee, D., Oh, E. -S., Woods, A., Couchman, J. R. & Lee, W. Solution structure of a syndecan-4 cytoplasmic domain and its interaction with phosphatidylinositol 4,5-bisphosphate. J. Biol. Chem. 273, 13022-13029 , (1998) .
    • . . . Structural analysis of a cytoplasmic-domain dimer has been completed for only syndecan 4 (Refs 16,17; Fig. 2) . . .
    • . . . Evidence indicates that the lipid binds this motif and stabilizes the syndecan-4 cytoplasmic domain in a dimeric form15, 16 (Fig. 2) . . .
    • . . . The syndecan dimer has an unusual twisted clamp motif where the two strands cross over each other at either end of the V region16, 17 . . .
  17. Shin, J. et al. Solution structure of the dimeric cytoplasmic domain of syndecan-4. Biochemistry 40, 8471-8478.This and the preceding paper provide the only structural data on a syndecan cytoplasmic domain , (2001) .
    • . . . Structural analysis of a cytoplasmic-domain dimer has been completed for only syndecan 4 (Refs 16,17; Fig. 2) . . .
    • . . . The syndecan dimer has an unusual twisted clamp motif where the two strands cross over each other at either end of the V region16, 17 . . .
  18. Lories, V., Cassiman, J. J., Van den Berghe, H. & David, G. Multiple distinct membrane heparan sulfate proteoglycans in human lung fibroblasts. J. Biol. Chem. 264, 7009-7016 , (1989) .
    • . . . Heterodimers between syndecan-family members are unknown, despite the similarity of their transmembrane sequences and the presence of multiple syndecans in many cell types (lung fibroblasts in culture might have all four18) . . .
  19. Baciu, P. C. et al. Syndesmos, a protein that interacts with the cytoplasmic domain of syndecan-4, mediates cell spreading and actin cytoskeletal organization. J. Cell Sci. 113, 315-324 , (2000) .
    • . . . Yeast two-hybrid analysis of cytoplasmic-domain interactions has, with one exception19, yielded only proteins that interact with the carboxy-terminal sequences of syndecans, but not C1- or V-region-binding proteins . . .
    • . . . Syndesmos, which was identified by yeast two-hybrid analyses, binds to the C1 region of syndecan 4, but has an added requirement for the V region19 . . .
  20. Filmus, J. & Selleck, S. B. Glypicans: proteoglycans with a surprise. J. Clin. Invest. 108, 497-501 , (2001) .
    • . . . Furthermore, no insight has so far come from genetic analysis of the single syndecans of C. elegans or Drosophila, unlike the situation with the other main family of cell-surface proteoglycans, the glypicans20. . . .
  21. Kato, M., Saunders, S., Nguyen, H. & Bernfield, M. Loss of cell surface syndecan-1 causes epithelia to transform into anchorage-independent mesenchyme-like cells. Mol. Biol. Cell 6, 559-576 , (1995) .
    • . . . Downregulation of syndecan 1 induced a fibroblastic morphology21 . . .
  22. Anttonnen, A., Kajanti, M., Heikkila, P., Jalkanen, M. & Joensuu, H. Syndecan-1 expression has prognostic significance in head and neck carcinoma. Br. J. Cancer 79, 558-564 , (1999) .
    • . . . There are several correlations between the loss of syndecan 1 and poorer prognosis of some head and neck carcinomas22, as well as the severity of the tumour grade in invasive cervical carcinoma23 . . .
  23. Rintala, M., Inki, P., Klemi, P., Jalkanen, M. & Grenman, S. Association of syndecan-1 with tumor grade and histology in primary invasive cervical carcinoma. Gynecol. Oncol. 75, 372-378 , (1999) .
    • . . . There are several correlations between the loss of syndecan 1 and poorer prognosis of some head and neck carcinomas22, as well as the severity of the tumour grade in invasive cervical carcinoma23 . . .
  24. Leppa, S., Vleminckx, K., Van Roy, F. & Jalkanen, M. Syndecan-1 expression in mammary epithelial tumor cells is E-cadherin-dependent. J. Cell Sci. 109, 1393-1403 , (1996) .
    • . . . It was subsequently discovered that loss of cell-surface syndecan 1 correlated with a loss of E-cadherin24 — a homotypic cell–cell adhesion receptor — and the likelihood of E-cadherin being a tumour suppressor25 is now under intense scrutiny . . .
  25. Berx, G. & Van Roy, F. The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression. Breast Cancer Res. 3, 289-293 , (2001) .
    • . . . It was subsequently discovered that loss of cell-surface syndecan 1 correlated with a loss of E-cadherin24 — a homotypic cell–cell adhesion receptor — and the likelihood of E-cadherin being a tumour suppressor25 is now under intense scrutiny . . .
  26. Carey, D. J., Stahl, R. C., Tucker, B., Bendt, K. A. & Cizmeci-Smith, G. Aggregation-induced association of syndecan-1 with microfilaments mediated by the cytoplasmic domain. Exp. Cell Res. 214, 12-21 , (1994) .
    • . . . Cadherins associate with the actin cytoskeleton but, although there is much circumstantial support that this provides the link to syndecans5, 14, 26, 27, no direct interactions between syndecan 1 and cytoskeletal proteins have been reported. . . .
  27. Miettinen, H. & Jalkanen, M. The cytoplasmic domain of syndecan-1 is not required for association with Triton-X-100-insoluble material. J. Cell Sci. 107, 1571-1581 , (1994) .
    • . . . Cadherins associate with the actin cytoskeleton but, although there is much circumstantial support that this provides the link to syndecans5, 14, 26, 27, no direct interactions between syndecan 1 and cytoskeletal proteins have been reported. . . .
  28. Kinnunen, T. et al. Cortactin-Src kinase signaling pathway is involved in N-syndecan-dependent neurite outgrowth. J. Biol. Chem. 273, 10702-10708 , (1998) .
    • . . . The C1 region of its cytoplasmic domain reportedly interacts with a complex that contains the tyrosine kinase Src and a potential substrate of Src, cortactin28 . . .
  29. Adams, J. C., Kureishy, N. & Taylor, A. L. A role for syndecan-1 in coupling fascin spike formation by thrombospondin-1. J. Cell Biol. 152, 1169-1182.A specific system for analysing the signalling pathway from syndecan 1 to the actin cytoskeleton and the role of GTPases , (2001) .
    • . . . Adams et al. showed that the process was syndecan-1 dependent29 . . .
  30. Dhodapkar, M. V. & Sanderson, R. D. Syndecan-1 (CD138) in myeloma and lymphoid malignancies: a multifunctional regulator of cell behavior within the tumor microenvironment. Leuk. Lymphoma 34, 35-43 , (1999) .
    • . . . Syndecan 1 is not restricted to epithelia — it is expressed in haematopoietic B-cell lineages, and in mice this expression is regulated through maturation30 . . .
  31. Dhodapkar, M. V. et al. Elevated levels of shed syndecan-1 correlate with tumour mass and decreased matrix metalloproteinase-9 activity in the serum of patients with multiple myeloma. Br. J. Haematol. 99, 368-371 , (1997) .
    • . . . Expression in some B-lymphoid malignancies such as multiple myeloma is also accompanied by syndecan-1 shedding and there is a correlation between tumour mass and serum levels of the proteoglycan31 . . .
    • . . . It certainly occurs in vivo31, 33, and can be brought about by one or more metalloproteinases that are sensitive to TIMP3 (tissue inhibitor of metalloproteinase 3; Ref. 34) . . .
  32. Yang, Y., Borset, M., Langford, J. K. & Sanderson, R. D. Heparan sulfate regulates targeting of syndecan-1 to a functional domain on the cell surface. J. Biol. Chem. 278, 12888-12893 , (2003) .
    • . . . In polarized, cultured B-lymphoid cells, syndecan 1 was recently shown to be localized to a membrane domain — the uropod32 — in a heparan-sulphate-dependent manner . . .
  33. Kainulainen, V., Wang, H., Schick, C. & Bernfield, M. Syndecans, heparan sulfate proteoglycans, maintain the proteolytic balance of acute wound fluid. J. Biol. Chem. 273, 11563-11569 , (1998) .
    • . . . It certainly occurs in vivo31, 33, and can be brought about by one or more metalloproteinases that are sensitive to TIMP3 (tissue inhibitor of metalloproteinase 3; Ref. 34) . . .
  34. Fitzgerald, M. L., Wang, Z., Park, P. W., Murphy, G. & Bernfield, M. Shedding of syndecan-1 and-4 ectodomains is regulated by multiple signaling pathways and mediated by a TIMP-3-sensitive metalloproteinase. J. Cell Biol. 148, 811-824 , (2000) .
    • . . . It certainly occurs in vivo31, 33, and can be brought about by one or more metalloproteinases that are sensitive to TIMP3 (tissue inhibitor of metalloproteinase 3; Ref. 34) . . .
  35. Dhodapkar, M. V. et al. Syndecan-1 is a multifunctional regulator of myeloma pathobiology: control of tumor cell survival, growth, and bone cell differentiation. Blood 91, 2679-2688 , (1998) .
    • . . . As might be expected, shed syndecan 1 can be inhibitory for some cellular functions, such as myeloma cell-line growth and osteogenesis35 . . .
  36. Kato, M. et al. Physiological degradation converts the soluble syndecan-1 ectodomain from an inhibitor to a potent activator of FGF-2. Nature Med. 4, 691-697 , (1998) .
    • . . . This is consistent with evidence that syndecan-1-shedding inhibits heparin-mediated fibroblast-growth-factor 2 (FGF2)-induced mitogenicity36 . . .
    • . . . However, platelet heparitinase can convert the shed syndecan 1 from an inhibitor to an activator36, which illustrates the potential complexity . . .
  37. Li, Q., Park, P. W., Wilson, C. L. & Parks, W. C. Matrilysin shedding of syndecan-1 regulates chemokines mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 111, 635-646.Elegant demonstration of how syndecan that is shed from the cell surface is functional in localizing an inflammatory response , (2002) .
    • . . . In turn, this directs and promotes transepithelial neutrophil migration37 . . .
  38. Ethell, I. M. & Yamaguchi, Y. Cell surface heparan sulfate proteoglycan syndecan-2 induces the maturation of dendritic spines in rat hippocampal neurons. J. Cell Biol. 144, 575-586 , (1999) .
    • . . . In neurons, syndecan 2 concentrates in DENDRITIC SPINES and experiments have shown that premature expression of the syndecan presages advanced development of spines in culture38, 39 . . .
    • . . . That the C2 region is important seems clear, because transfection with syndecan 2 that lacks this carboxy-terminal sequence does not mediate early maturation of dendritic spines38 . . .
    • . . . CASK and syndecan 2 are probably targeted to common epithelial membrane domains, and work with syndecan-2 truncations shows that mistargeting correlates with loss of the C2 region38 . . .
  39. Ethell, I. M. et al. EphB/syndecan-2 signaling in dendritic spine morphogenesis. Neuron 31, 1001-1013.Lateral association of syndecan 2 with the Eph receptor tyrosine kinase provides a basis for syndecan phosphorylation and clustering associated with dendritic maturation , (2001) .
    • . . . In neurons, syndecan 2 concentrates in DENDRITIC SPINES and experiments have shown that premature expression of the syndecan presages advanced development of spines in culture38, 39 . . .
    • . . . Syndecan 2 in these spines can associate with, and be phosphorylated by, the EphB2 receptor tyrosine kinase39 . . .
    • . . . The functional consequences of tyrosine phosphorylation are, therefore, not resolved, but clustering of syndecan 2 in spines, and the maturation of the spines, depends on the tyrosine-kinase activity of EphB2 (Ref. 39) . . .
    • . . . Moreover, syndecan 2 forms a complex with CASK and EphB2 receptor tyrosine kinase39 in postsynaptic membranes . . .
  40. Ethell, I. M., Hagihara, K., Miura, Y., Irie, F. & Yamaguchi, Y. Synbindin, a novel syndecan-2-binding protein in neuronal dendritic spines. J. Cell Biol. 151, 53-67 , (2000) .
    • . . . Clustering might promote interactions of the carboxyl terminus of syndecan 2 with synbindin40 and/or CASK (calcium/calmodulin-dependent serine protein kinase, also known as LIN2; Refs 41,42), which stabilize the complex (Fig. 4) . . .
    • . . . Since then, CASK41, 42, synbindin40 and synectin (SEMCAP1, semaphorin F cytoplasmic-domain-associated protein; Ref. 87) have all been reported to bind syndecan cytoplasmic domains, but our knowledge of their binding properties is far from complete . . .
    • . . . It might regulate vesicle trafficking40 . . .
  41. Cohen, A. R. et al. Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells. J. Cell Biol. 142, 129-138 , (1998) .
    • . . . Clustering might promote interactions of the carboxyl terminus of syndecan 2 with synbindin40 and/or CASK (calcium/calmodulin-dependent serine protein kinase, also known as LIN2; Refs 41,42), which stabilize the complex (Fig. 4) . . .
    • . . . Since then, CASK41, 42, synbindin40 and synectin (SEMCAP1, semaphorin F cytoplasmic-domain-associated protein; Ref. 87) have all been reported to bind syndecan cytoplasmic domains, but our knowledge of their binding properties is far from complete . . .
  42. Hsueh, Y. -P. & Sheng, M. Regulated expression and subcellular localization of syndecan heparan sulfate proteoglycans and the syndecan-binding protein CASK/LIN-2 during rat brain development. J. Neurosci. 19, 7415-7425 , (1999) .
    • . . . Clustering might promote interactions of the carboxyl terminus of syndecan 2 with synbindin40 and/or CASK (calcium/calmodulin-dependent serine protein kinase, also known as LIN2; Refs 41,42), which stabilize the complex (Fig. 4) . . .
    • . . . Since then, CASK41, 42, synbindin40 and synectin (SEMCAP1, semaphorin F cytoplasmic-domain-associated protein; Ref. 87) have all been reported to bind syndecan cytoplasmic domains, but our knowledge of their binding properties is far from complete . . .
  43. Irie, F. & Yamaguchi, Y. EphB receptors regulate dendritic spine development via intersectin, Cdc42 and N-WASP. Nature Neurosci. 5, 1117-1118 , (2002) .
    • . . . The actin cytoskeletal changes that occur in spine maturation seem to involve EphB2-mediated regulation of the Rho GTPase Cdc42 (Ref. 43). . . .
  44. Klass, C. M., Couchman, J. R. & Woods, A. Control of extracellular matrix assembly by syndecan-2 proteoglycan. J. Cell Sci. 113, 493-506 , (2000) .
    • . . . Work with Chinese hamster ovary (CHO) cells shows that ECM assembly is disrupted by transfection with syndecan 2 that is truncated midway through the V region44 . . .
    • . . . Expressing syndecan 2 with a truncation midway through the V region (as described above44), Kramer and Yost found that heart and gut looping was randomized51 . . .
  45. Cukierman, E., Pankov, R., Stevens, D. R. & Yamada, K. M. Taking cell-matrix adhesions to the third dimension. Science 294, 1661-1663 , (2001) .
    • . . . However, matrix-assembly points are distinct membrane microdomains45 . . .
  46. Granés, F., Ureña, J. M., Rocamora, N. & Vilaró, S. Ezrin links syndecan-2 to the cytoskeleton. J. Cell Sci. 113, 1267-1276 , (2000) .
    • . . . What is known regarding syndecan-2 interactions with cytoplasmic components? It has been reported that ezrin, an actin-binding submembranous protein of the ezrin–radixin–moesin (ERM) family, interacts with syndecan 2 (Ref. 46), probably in its C1 region . . .
  47. Granés, F. et al. Syndecan-2 induces filopodia by active cdc42Hs. Exp. Cell Res. 248, 439-456 , (1999) .
    • . . . Moreover, it has been suggested47 that signalling through syndecan 2 is mediated by Cdc42 . . .
  48. Kusano, Y. et al. Participation of syndecan 2 in the induction of stress fiber formation in cooperation with integrin 51: structural characteristics of heparan sulfate chains with avidity to COOH-terminal heparin-binding domain of fibronectin. Exp. Cell Res. 256, 434-444 , (2000) .
    • . . . To complicate matters further, it has recently been reported that syndecan 2 can promote focal-adhesion formation in Lewis-lung-carcinoma clones48, 49 . . .
  49. Munesue, S. et al. The role of syndecan-2 in regulation of actin-cytoskeletal organization of Lewis lung carcinoma-derived metastatic clones. Biochem. J. 363, 201-209 , (2002) .
    • . . . To complicate matters further, it has recently been reported that syndecan 2 can promote focal-adhesion formation in Lewis-lung-carcinoma clones48, 49 . . .
  50. Woods, A & Couchman, J. R. Syndecan-4 and focal adhesion function. Curr. Opin. Cell Biol. 13, 578-583 , (2001) .
    • . . . This process also occurs in other cell types7, 50 . . .
    • . . . It might also be regulating its close cousin, syndecan 4, which does have a role in focal-adhesion formation in primary, non-transformed fibroblasts50. . . .
    • . . . One advantage is that it is present in the focal adhesions of several cell types7, 50, 57, 58 . . .
    • . . . At present, therefore, it is suspected that syndecan 4, PKC and the phospholipid form a ternary signalling complex that is localized to the nascent focal adhesions7, 50, 67, 68 (Fig. 6) . . .
    • . . . Syndecan-4 signalling might lead to the activation of RhoA75, which is entirely consistent with both proteins having a known role in promoting the formation of microfilament bundles and, concomitantly, focal adhesions50, 76 . . .
  51. Kramer, K. L. & Yost, H. J. Ectodermal syndecan-2 mediates left-right axis formation in migrating mesoderm as a cell-nonautonomous Vg1 cofactor. Dev. Cell 2, 115-124 , (2002) .
    • . . . However, very recent work on Xenopus laevis development has provided an altogether new outlook on syndecan 2 (Refs 51,52) . . .
    • . . . Expressing syndecan 2 with a truncation midway through the V region (as described above44), Kramer and Yost found that heart and gut looping was randomized51 . . .
    • . . . Further analysis implied that presentation or activation of the transforming-growth-factor- (TGF)-family member vitellogenin 1 (Vg1) was defective51 . . .
  52. Kramer, K. L., Barnette, J. E. & Yost, H. J. PKC regulates syndecan-2 inside-out signaling during Xenopus left-right development. Cell 111, 981-990.References 51 and 52 provide not only evidence for the role of syndecan 2 in early vertebrate development, but also a molecular basis for the signalling process , (2002) .
    • . . . However, very recent work on Xenopus laevis development has provided an altogether new outlook on syndecan 2 (Refs 51,52) . . .
    • . . . Yost's group has also determined that protein kinase C (PKC) lies upstream of syndecan 2 in determining left–right asymmetry in Xenopus embryos52 . . .
  53. Tumova, S., Woods, A. & Couchman, J. R. Heparan sulfate chains from glypican and syndecans bind Hep II domain of fibronectin similarly despite minor structural differences. J. Biol. Chem. 275, 9410-9417 , (2000) .
    • . . . Although this is quite possible, no evidence of such exquisite specificity has yet been described, and so far, heparan-sulphate chains from syndecans of the same cell type look remarkably similar53, 54 . . .
  54. Zako, M. et al. Syndecan-1 and -4 synthesized simultaneously by mouse mammary gland epithelial cells bear heparan sulfate chains that are apparently structurally indistinguishable. J. Biol. Chem. 278, 13561-13569 , (2003) .
    • . . . Although this is quite possible, no evidence of such exquisite specificity has yet been described, and so far, heparan-sulphate chains from syndecans of the same cell type look remarkably similar53, 54 . . .
  55. Calderwood, D. A. Shattil, S. J. & Ginsberg, M. H. Integrins and actin filaments: reciprocal regulation of cell adhesion and signaling. J. Biol. Chem. 275, 22607-22610 , (2000) .
    • . . . This represents the first case of inside–out signalling through a syndecan, a process that is known to occur in other receptors, particularly integrins55 . . .
  56. Oh, E. -S., Couchman, J. R. & Woods, A. Serine phosphorylation of syndecan-2 proteoglycan cytoplasmic domain. Arch. Biochem. Biophys. 344, 67-74 , (1997) .
    • . . . The question now is what impact phosphorylation of the serine residues has on syndecan 2 and its ability to signal to the mesendoderm? Perhaps phosphorylation regulates oligomerization of the syndecan, although previous in vitro studies have not found such a mechanism56 . . .
  57. Woods, A. & Couchman, J. R. Syndecan 4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion component. Mol. Biol. Cell 5, 183-192 , (1994) .
    • . . . One advantage is that it is present in the focal adhesions of several cell types7, 50, 57, 58 . . .
  58. Baciu, P. C. & Goetinck, P. F. Protein kinase C regulates the recruitment of syndecan-4 into focal contacts. Mol. Biol. Cell 6, 1503-1513 , (1995) .
    • . . . One advantage is that it is present in the focal adhesions of several cell types7, 50, 57, 58 . . .
    • . . . Whether syndesmos, a widespread protein, has a direct role in focal-adhesion formation is not yet clear, but, as PKC activity correlates with syndecan-4 recruitment into forming adhesions58, this is certainly a possibility. . . .
  59. Longley, R. L. et al. Control of morphology, cytoskeleton and migration by syndecan-4. J. Cell Sci. 112, 3421-3431 , (1999) .
    • . . . Overexpression of syndecan 4 in CHO cells leads to increased focal-adhesion assembly, in terms of their numbers and size59 . . .
    • . . . Once again, a truncation through the V region of the cytoplasmic domain has a DOMINANT-NEGATIVE effect — in this case, there is reduced cell spreading and focal-adhesion formation59 . . .
  60. Oh, E. -S., Woods, A., Lim, S. -T., Theibert, A. W. & Couchman, J. R. Syndecan-4 proteoglycan cytoplasmic domain and phosphatidylinositol 4,5-bisphosphate co-ordinately regulate protein kinase C activity. J. Biol. Chem. 273, 10624-10629 , .
    • . . . The complex can then bind and strongly activate PKC60, 62, 63, 64 . . .
    • . . . Moreover, it is the carboxy-terminal region of the catalytic domain of PKC that is responsible; the regulatory domain of PKC binds PtdIns(4,5)P2 (Ref. 66), and on its own is a partial activator60 . . .
    • . . . PKC activation by this route has an additional nuance; it seems to be calcium-independent, at least in vitro60, 61 . . .
  61. Horowitz, A., Murakami, M., Gao, Y. & Simons, M. Phosphatidylinositol-4,5-bisphosphate mediates the interaction of syndecan-4 with protein kinase C. Biochemistry 38, 15871-15877 , (1999) .
    • . . . An alternative view is that PtdIns(4,5)P2 bridges between the syndecan-4 cytoplasmic domain and the kinase61 . . .
    • . . . PKC activation by this route has an additional nuance; it seems to be calcium-independent, at least in vitro60, 61 . . .
  62. Couchman, J. R. et al. Regulation of inositol phospholipid binding and signaling through syndecan-4. J. Biol. Chem. 277, 49296-49303 , (2002) .
    • . . . The complex can then bind and strongly activate PKC60, 62, 63, 64 . . .
  63. Oh, E. -S., Woods, A. & Couchman, J. R. Syndecan-4 proteoglycan regulates the distribution and activity of protein kinase C. J. Biol. Chem. 272, 8133-8136 , (1997) .
    • . . . The complex can then bind and strongly activate PKC60, 62, 63, 64 . . .
    • . . . This interaction is direct, as shown by yeast two-hybrid analysis and consistent with biochemical analysis63 . . .
  64. Horowitz, A. & Simons, M. Phosphorylation of the cytoplasmic tail of syndecan-4 regulates activation of protein kinase C. J. Biol. Chem. 273, 25548-25551 , (1998) .
    • . . . The complex can then bind and strongly activate PKC60, 62, 63, 64 . . .
    • . . . Horowitz and Simons reported that the single serine residue in the C1 region of the cytoplasmic domain of syndecan 4 can be phosphorylated in response to growth inhibition64, 70 . . .
  65. Lim, S. -T., Longley, R. L., Couchman, J. R. & Woods, A. Direct binding of syndecan-4 cytoplasmic domain to the catalytic domain of PKC increases focal adhesion localization of PKC. J. Biol. Chem. 278, 13795-13802.This brings together evidence for a role for syndecan 4 in focal-adhesion formation and the localization of PKC , (2003) .
    • . . . This correlates both with a requirement for PKC activity in cell adhesion, and the presence of the isoform in the focal adhesions of some non-transformed cells65 . . .
    • . . . Overexpression of syndecan 4 dramatically increases detectable PKC in focal adhesions, indicating that the kinase is localized there by virtue of its syndecan 4 interactions65 . . .
  66. Corbal´n-Garc'a, S., Garc'a-Garc'a, J., Rodr'guez-Alfaro, J. A. & Gómez-Fernández, J. C. A new phosphatidylinositol 4,5-bisphoshate-binding site located in the C2 domain of protein kinase C. J. Biol. Chem. 278, 4972-4980 , (2003) .
    • . . . Moreover, it is the carboxy-terminal region of the catalytic domain of PKC that is responsible; the regulatory domain of PKC binds PtdIns(4,5)P2 (Ref. 66), and on its own is a partial activator60 . . .
  67. Woods, A. & Couchman, J. R. Integrin modulation by lateral association. J. Biol. Chem. 275, 24233-24236 , (2000) .
    • . . . At present, therefore, it is suspected that syndecan 4, PKC and the phospholipid form a ternary signalling complex that is localized to the nascent focal adhesions7, 50, 67, 68 (Fig. 6) . . .
  68. Bass, M. D., & Humphries, M. J. Cytoplasmic interactions of Syndecan-4 orchestrate adhesion receptor and growth factor receptor signalling. Biochem. J. 368, 1-15 , (2002) .
    • . . . At present, therefore, it is suspected that syndecan 4, PKC and the phospholipid form a ternary signalling complex that is localized to the nascent focal adhesions7, 50, 67, 68 (Fig. 6) . . .
    • . . . Addition of LYSOPHOSPHATIDIC ACID, a known activator of RhoA, subsequently promoted these structures68, 76 . . .
  69. Bhatt, A., Kaverina, I., Otey, C. & Huttenlocher, A. Regulation of focal complex composition and disassembly by the calcium-dependent calpain. J. Cell Sci. 115, 3415-3425 , (2002) .
    • . . . It might be that the absence of calcium fluxes around nascent focal adhesions avoids activating calmodulin-mediated responses, such as those that involve myosin, or prevents the activation of calpain, a calcium-dependent proteinase that might promote focal-adhesion disassembly69 . . .
  70. Horowitz, A. & Simons, M. Regulation of syndecan-4 phosphorylation in vivo. J. Biol. Chem. 273, 10914-10918 , (1998) .
    • . . . Horowitz and Simons reported that the single serine residue in the C1 region of the cytoplasmic domain of syndecan 4 can be phosphorylated in response to growth inhibition64, 70 . . .
  71. Murakami, M., Horowitz, A., Tang, S., Ware, J. A. & Simons, M. Protein kinase C (PKC) regulates PKC activity in a syndecan-4-dependent manner. J. Biol. Chem. 277, 20367-20371 , (2002) .
    • . . . The kinase responsible for serine phosphorylation was suggested to be PKC — a novel PKC isoform71 — but the net result was a markedly decreased affinity of the downstream V region for PtdIns(4,5)P2 and, concomitantly, diminished PKC activation . . .
  72. Denhez, F. et al. Syndesmos, a syndecan-4 cytoplasmic domain interactor, binds to the focal adhesion adaptor proteins paxillin and Hic-5. J. Biol. Chem. 277, 12270-12274 , (2002) .
    • . . . It also interacts with the paxillin homologue Hic5 (Ref. 72) . . .
  73. Greene, D. K., Tumova, S., Couchman, J. R. & Woods, A. Syndecan-4 associates with -actinin. J. Biol. Chem. 278, 7617-7623 , (2003) .
    • . . . Evidence of direct binding of cytoskeletal proteins to syndecan 4 has been elusive, apart from some recent data with -actinin73 . . .
    • . . . This actin-bundling protein binds several focal-adhesion components including -integrins, vinculin, zyxin and PtdIns(4,5)P2 (Ref. 74), but it seems to interact directly, and in a detergent-resistant manner, with the syndecan-4 V region, which indicates that it has a functional role in the focal adhesion73 . . .
  74. Critchley, D. R. Focal adhesions - the cytoskeletal connection. Curr. Opin. Cell Biol. 12, 133-139 , (2000) .
    • . . . This actin-bundling protein binds several focal-adhesion components including -integrins, vinculin, zyxin and PtdIns(4,5)P2 (Ref. 74), but it seems to interact directly, and in a detergent-resistant manner, with the syndecan-4 V region, which indicates that it has a functional role in the focal adhesion73 . . .
  75. Saoncella, S. et al. Syndecan-4 signals cooperatively with integrins in a Rho-dependent manner in the assembly of focal adhesions and actin stress fibers. Proc. Natl Acad. Sci. USA 96, 2805-2810 , (1999) .
    • . . . Syndecan-4 signalling might lead to the activation of RhoA75, which is entirely consistent with both proteins having a known role in promoting the formation of microfilament bundles and, concomitantly, focal adhesions50, 76 . . .
  76. Bishop, A. & Hall, A. Rho GTPases and their effector proteins. Biochem. J. 348, 241-255 , (2000) .
    • . . . Syndecan-4 signalling might lead to the activation of RhoA75, which is entirely consistent with both proteins having a known role in promoting the formation of microfilament bundles and, concomitantly, focal adhesions50, 76 . . .
    • . . . Addition of LYSOPHOSPHATIDIC ACID, a known activator of RhoA, subsequently promoted these structures68, 76 . . .
    • . . . These gaps need to be filled, but the downstream events of RhoA activation probably involve the activation of Rho kinases (ROCKs), which can phosphorylate myosin light chain and myosin light-chain phosphatase, leading to myosin activation and microfilament contractions76, 80 (Fig. 6) . . .
  77. Slater, S. J., Seiz, J. L., Stagliano, B. A. & Stubbs, C. D. Interaction of protein kinase C isozymes with Rho GTPases. Biochemistry 40, 4437-4445 , (2001) .
    • . . . The molecular mechanism behind RhoA activation remains unknown, but it has been suggested that many PKC isoforms and RhoA can directly interact77 . . .
  78. Defilippi, P. et al. Dissection of pathways implicated in integrin-mediated actin cytoskeleton assembly. Involvement of protein kinase C, Rho GTPase, and tyrosine phosphorylation. J. Biol. Chem. 272, 21726-21734 , (1997) .
    • . . . Other work indicates that PKC activity and RhoA are both required, but in separate pathways, for full adhesion78, 79 . . .
  79. Thodeti, C. K. et al. ADAM12/syndecan-4 signaling promotes 1 integrin-dependent cell spreading through PKC and Rho A. J. Biol. Chem. 278, 9576-9584 , (2003) .
    • . . . Other work indicates that PKC activity and RhoA are both required, but in separate pathways, for full adhesion78, 79 . . .
  80. Fukata, Y., Amano, M. & Kaibuchi, K. Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol. Sci. 22, 32-39 , (2001) .
    • . . . These gaps need to be filled, but the downstream events of RhoA activation probably involve the activation of Rho kinases (ROCKs), which can phosphorylate myosin light chain and myosin light-chain phosphatase, leading to myosin activation and microfilament contractions76, 80 (Fig. 6) . . .
  81. Watanabe, N. et al. p140mDia, a mammalian homolog of Drosophila diaphanous, is a target protein for Rho small GTPase and is a ligand for profilin. EMBO J. 16, 3044-3056 , (1997) .
    • . . . An alternative pathway from RhoA involves Dia (diaphanous), which regulates actin polymerization through the agency of profilin81. . . .
  82. Stanley, M. J., Liebersbach, B. F., Liu, W., Anhalt, D. J. & Sanderson, R. D. Heparan sulfate-mediated cell aggregation. Syndecans-1 and-4 mediate intercellular adhesion following their transfection into human B lymphoid cells. J. Biol. Chem. 270, 5077-5083 , (1995) .
    • . . . In a series of B-lymphoid lines, both syndecan 1 and syndecan 4 were shown to promote intercellular adhesion82, but the molecular interactions are unknown . . .
  83. Fuki I. V. et al. The syndecan family of proteoglycans. Novel receptors mediating internalization of atherogenic lipoproteins in vitro. J. Clin. Invest. 100, 1611-1622 , (1997) .
    • . . . Interactions of lipoprotein lipase with syndecan 1, and FGF2 with syndecan 4 indicate a common downstream pathway that involves cholesterol-rich membrane rafts83, 84, 85 . . .
  84. Fuki, I. V., Meyer, M. E. & Williams, K. J. Transmembrane and cytoplasmic domains of syndecan mediate a multi-step endocytic pathway involving detergent-insoluble membrane rafts. Biochem. J. 351, 607-612.The importance of syndecan clustering and translocation to a membrane domain following ligand binding is illustrated , (2000) .
    • . . . Interactions of lipoprotein lipase with syndecan 1, and FGF2 with syndecan 4 indicate a common downstream pathway that involves cholesterol-rich membrane rafts83, 84, 85 . . .
    • . . . In one case, controls showed an involvement of the actin cytoskeleton and tyrosine kinase(s) in this process, but a separation of cytoskeletal linkage from detergent insolubility84 . . .
    • . . . The data with syndecan 1 indicate a mechanism that might involve CAVEOLAE84, yet the syndecan-4 study showed no co-localization with caveolin 1 (Ref. 85) . . .
  85. Tkachenko, E. & Simons, M. Clustering induces redistribution of syndecan-4 core protein into raft membrane domains. J. Biol. Chem. 277, 19946-19951 , (2002) .
    • . . . Interactions of lipoprotein lipase with syndecan 1, and FGF2 with syndecan 4 indicate a common downstream pathway that involves cholesterol-rich membrane rafts83, 84, 85 . . .
    • . . . The data with syndecan 1 indicate a mechanism that might involve CAVEOLAE84, yet the syndecan-4 study showed no co-localization with caveolin 1 (Ref. 85) . . .
  86. Grootjans, J. J. et al. Syntenin, a PDZ protein that binds syndecan cytoplasmic domains. Proc. Natl Acad. Sci. USA 94, 13683-13688 , (1997) .
    • . . . The first to be identified was syntenin86, which binds all four vertebrate syndecans . . .
    • . . . Syntenin can bind disparate cell-surface molecules, including ephrin-B proteins, neurexin, a series of glutamate receptors, and pro-TGF-, as well as all four mammalian syndecans86, 88 . . .
    • . . . However, although overexpression of syntenin affects the cytoskeleton (and becomes concentrated in vesicles), the molecular basis for this property is undefined86 . . .
  87. Gao, Y., Li, M., Chen, W. & Simons, M. Synectin, syndecan-4 cytoplasmic domain binding PDZ protein, inhibits cell migration. J. Cell Physiol. 184, 373-379 , (2000) .
    • . . . Since then, CASK41, 42, synbindin40 and synectin (SEMCAP1, semaphorin F cytoplasmic-domain-associated protein; Ref. 87) have all been reported to bind syndecan cytoplasmic domains, but our knowledge of their binding properties is far from complete . . .
    • . . . In this regard it has recently been reported that synectin/SEMCAP1 binds not only syndecan 4 (Ref. 87), but also 5- and 6-integrins, which themselves can become localized to focal adhesions, depending on the ECM substrate92 . . .
  88. Hung, A. Y. & Sheng, M. PDZ domains: structural modules for protein complex assembly. J. Biol. Chem. 277, 5699-5702 , (2002) .
    • . . . As a group, PDZ proteins seem to be scaffolding proteins, containing a variable number of PDZ motifs88 . . .
    • . . . Syntenin can bind disparate cell-surface molecules, including ephrin-B proteins, neurexin, a series of glutamate receptors, and pro-TGF-, as well as all four mammalian syndecans86, 88 . . .
    • . . . The C. elegans homologue of CASK, Lin2, reportedly functions in basolateral targeting of an epidermal growth factor receptor, Let23, and mammalian CASK binds syndecan 1, syndecan 2 and syndecan 3 (Ref. 88) . . .
    • . . . By contrast, CASK, at least in C. elegans, has been implicated in basolateral targeting88 . . .
  89. Zimmermann, P. et al. Characterization of syntenin, a syndecan-binding PDZ protein, as a component of cell adhesion sites and microfilaments. Mol. Biol. Cell 12, 339-350 , (2001) .
    • . . . David's group have shown that syntenin is present proximal to focal adhesions and adherens junctions, associating in the latter with syndecan 1 (Ref. 89) . . .
  90. Fialka, I. et al. Identification of syntenin as a protein of the apical early endocytic compartment in Madin-Darby canine kidney cells. J. Biol. Chem. 274, 26233-26239 , (1999) .
    • . . . Syntenin was identified as an apical early endosome component in Madin–Darby canine kidney (MDCK) cells, but was found not to be associated with basolateral vesicles90 . . .
  91. Lin, D., Gish, G. D., Songyang, Z. & Pawson, T. The carboxyl terminus of B class ephrins constitutes a PDZ domain binding motif. J. Biol. Chem. 274, 3726-3733 , (1999) .
    • . . . The ligands for EphB2 on the presynaptic membrane are ephrin-B molecules, which themselves can bind to syntenin91 . . .
  92. El Mourabit, H. et al. The PDZ domain of TIP-2/GIPC interacts with the C-terminus of the integrin 5 and 6 subunits. Matrix Biol. 21, 207-214 , (2002) .
    • . . . In this regard it has recently been reported that synectin/SEMCAP1 binds not only syndecan 4 (Ref. 87), but also 5- and 6-integrins, which themselves can become localized to focal adhesions, depending on the ECM substrate92 . . .
  93. Stepp, M. A. et al. Defects in keratinocyte activation during wound healing in the syndecan-1-deficient mouse. J. Cell Sci. 115, 4517-4531 , (2002) .
    • . . . Consistent with a prominent epidermal distribution, syndecan-1-null mice re-epithelialize slowly93, and also show an increased adhesiveness of leukocytes to the endothelium94 . . .
  94. Götte, M. et al. Role of syndecan-1 in leukocyte-endothelial interactions in the ocular vasculature. Invest. Ophthalmol. Vis. Sci. 34, 1135-1141 , (2002) .
    • . . . Consistent with a prominent epidermal distribution, syndecan-1-null mice re-epithelialize slowly93, and also show an increased adhesiveness of leukocytes to the endothelium94 . . .
  95. Alexander, C. M., Hinkes, M. T. & Bernfield, M. Syndecan-1 is required for Wnt-1-induced tumorigenesis but not for morphogenesis of mouse mammary epithelia. Nature Genet. 25, 329-332 , (2000) .
    • . . . Mice with mammary-gland-specific transgenic expression of Wnt1 develop mammary tumours, but not if syndecan 1 is absent95 . . .
  96. Stanley, M. J., Stanley, M. W., Sanderson, R. D. & Zera, R. Syndecan-1 expression is induced in the stroma of infiltrating breast carcinoma. Am. J. Clin. Pathol. 112, 377-383 , (1999) .
    • . . . Moreover, in human breast carcinoma, syndecan 1 is expressed in the stroma, where it is normally absent in non-transformed tissue, but is often also absent from the infiltrating ductal epithelial cells, where it is present in the normal counterparts96 . . .
  97. Echtermeyer, F. et al. Delayed wound repair and impaired angiogenesis in mice lacking syndecan-4. J. Clin. Invest. 107, R9-R14 , (2001) .
    • . . . In these processes, there are defects in GRANULATION TISSUE angiogenesis that even occur in heterozygous animals97 . . .
  98. Ishiguro, K. et al. Syndecan-4 deficiency impairs focal adhesion formation only under restricted conditions. J. Biol. Chem. 275, 5249-5252 , (2000) .
    • . . . Other experiments have shown that null fibroblasts spread and form focal adhesions on fibronectin98 . . .
  99. Ishiguro, K. et al. Syndecan-4 deficiency leads to high mortality of lipopolysaccharide-injected mice. J. Biol. Chem. 276, 47483-47488 , (2001) .
    • . . . Compared with normal controls, syndecan-4-null mice succumb to the effects of LIPOPOLYSACCHARIDE injection to a much greater degree99 . . .
  100. Ishiguro, K. et al. Syndecan-4 deficiency increases susceptibility to -carrageenan-induced renal damage. Lab. Invest. 81, 509-516 , (2001) .
    • . . . Another study shows increased susceptibility to kidney damage after CARRAGEENAN injection into syndecan-4-null mice100, which is again indicative of a relationship between syndecan 4, the vascular system and inflammation . . .
  101. Yung, S. et al. Syndecan-4 up-regulation in proliferative renal disease is related to microfilament organization. FASEB J. 15, 1631-1633 , (2001) .
    • . . . Indeed, after myocardial infarction, patients have high levels of circulating syndecan 4, and in another study, syndecan 4 is upregulated in the kidney cortex of patients with IgA nephropathy101 . . .
  102. Zhang, Y., Pasparakis, M., Kollias, G. & Simons, M. Myocyte-dependent regulation of endothelial cell syndecan-4 expression. Role of TNF-. J. Biol. Chem. 274, 14786-14796 , (1999) .
    • . . . HYPOXIA seems to be a powerful stimulus for syndecan-4 expression, possibly stimulated by tumour necrosis factor (TNF-; Ref. 102) . . .
  103. Cizmeci-Smith, G., Langan, E., Youkey, J., Showalter, L. J. & Carey, D. J. Syndecan-4 is a primary-response gene induced by basic fibroblast growth factor and arterial injury in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 17, 172-180 , (1997) .
    • . . . Evidence indicates that syndecan 4 is an early response gene in vascular injury103. . . .
  104. Lindahl, U., Kusche-Gullberg, M. & Kjellén, L. Regulated diversity of heparan sulfate. J. Biol. Chem. 273, 24979-24982 , (1998) .
  105. Esko, J. D. & Lindahl, U. Molecular diversity of heparan sulfate. J. Clin. Invest. 108, 169-173 , (2001) .
  106. Esko, J. D. & Selleck, S. B. Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu. Rev. Biochem. 71, 435-471 , (2002) .
  107. Van Kuppevelt, T. H., Dennissen, M. A., van Venrooij, W. J. Hoet, R. M. & Veerkamp, J. H. Generation and application of type-specific anti-heparan sulfate antibodies using phage display technology. Further evidence for heparan sulfate heterogeneity in the kidney. J. Biol. Chem. 273, 12960-12966 , (1998) .
  108. Gallagher, J. T. Heparan sulfate: growth control with a restricted sequence menu. J. Clin. Invest. 108, 357-361 , (2001) .
  109. Lander, A. D. Proteoglycans: master regulators of molecular encounter? Matrix Biol. 17, 465-472 , (1998) .
  110. Fanning, A. S. & Anderson, J. M. PDZ domains: fundamental building blocks in the organization of protein complexes at the plasma membrane. J. Clin. Invest. 103, 767-772 , (1999) .
  111. Zimmermann, P. et al. PIP2-PDZ domain binding controls the association of syntenin with the plasma membrane. Mol. Cell 9, 1215-1225 , (2002) .
Expand