Fibroblast growth factor–specific modulation of cellular response by syndecan-4

Proteoglycans participate in growth factor interaction with the cell surface through their heparan sulfate chains (HS), but it is not known if they are otherwise involved in growth factor signaling. It appears now that the syndecan-4 core protein, a transmembrane proteoglycan shown previously to bind phosphatidylinositol 4,5-bisphosphate (PIP2) and activate PKCα, participates in mediating the effects of fibroblast growth factor (FGF)2 on cell function. Mutations in the cytoplasmic tail of syndecan-4 that either reduced its affinity to PIP2 (PIP2 −) or disrupted its postsynaptic density 95, disk large, zona occludens-1 (PDZ)-dependent binding (PDZ−) produced a FGF2-specific dominant negative phenotype in endothelial cells as evidenced by the marked decline of their migration and proliferation rates and the impairment of their capacity to form tubes. In both cases, the molecular mechanism was determined to consist of a decrease in the syndecan-4–dependent activation of PKCα. This decrease was caused either by inhibition of FGF2-induced syndecan-4 dephosphorylation in the case of the PDZ− mutation or by disruption of basolateral targeting of syndecan-4 and its associated PDZ-dependent complex in the case of the PIP2 − mutation. These results suggest that PKCα activation and PDZ-mediated formation of a serine/threonine phosphatase-containing complex by syndecan-4 are downstream events of FGF2 signaling.

[1]  W. Kolch,et al.  Protein kinase C alpha activates RAF-1 by direct phosphorylation. , 1993, Nature.

[2]  L. Cantley,et al.  Recognition of Unique Carboxyl-Terminal Motifs by Distinct PDZ Domains , 1997, Science.

[3]  G. Warren,et al.  Characterization of a cis-Golgi matrix protein, GM130 , 1995, The Journal of cell biology.

[4]  M. Simons,et al.  Regulation of Syndecan-4 Phosphorylation in Vivo * , 1998, The Journal of Biological Chemistry.

[5]  T. Hawley,et al.  Versatile retroviral vectors for potential use in gene therapy. , 1994, Gene therapy.

[6]  G. Bren,et al.  Activation of IκB Kinase β by Protein Kinase C Isoforms , 1999, Molecular and Cellular Biology.

[7]  Weontae Lee,et al.  Solution Structure of a Syndecan-4 Cytoplasmic Domain and Its Interaction with Phosphatidylinositol 4,5-Bisphosphate* , 1998, The Journal of Biological Chemistry.

[8]  L. Brown,et al.  Macrophage-dependent regulation of syndecan gene expression. , 1997, Circulation research.

[9]  C. Marshall,et al.  Activation of the Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Pathway by Conventional, Novel, and Atypical Protein Kinase C Isotypes , 1998, Molecular and Cellular Biology.

[10]  A. Horowitz,et al.  Phosphorylation of the Cytoplasmic Tail of Syndecan-4 Regulates Activation of Protein Kinase Cα* , 1998, The Journal of Biological Chemistry.

[11]  G. Martiny-Baron,et al.  Selective inhibition of protein kinase C isozymes by the indolocarbazole Gö 6976. , 1993, The Journal of biological chemistry.

[12]  R. Mulligan,et al.  Characterization of ryudocan glycosaminoglycan acceptor sites. , 1994, The Journal of biological chemistry.

[13]  S. Lim,et al.  Syndecan-4 Proteoglycan Cytoplasmic Domain and Phosphatidylinositol 4,5-Bisphosphate Coordinately Regulate Protein Kinase C Activity* , 1998, The Journal of Biological Chemistry.

[14]  P. Baciu,et al.  Protein kinase C regulates the recruitment of syndecan-4 into focal contacts. , 1995, Molecular biology of the cell.

[15]  M. Simons,et al.  Phosphatidylinositol-4,5-bisphosphate mediates the interaction of syndecan-4 with protein kinase C. , 1999, Biochemistry.

[16]  M. Klagsbrun,et al.  Syndecans, cell surface heparan sulfate proteoglycans, are induced by a proline-rich antimicrobial peptide from wounds. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[17]  J. J. Schwartz,et al.  The Role of Syndecan Cytoplasmic Domain in Basic Fibroblast Growth Factor-dependent Signal Transduction* , 1999, The Journal of Biological Chemistry.

[18]  James M. Anderson,et al.  Human CASK/LIN-2 Binds Syndecan-2 and Protein 4.1 and Localizes to the Basolateral Membrane of Epithelial Cells , 1998, The Journal of cell biology.

[19]  I. Ethell,et al.  Cell Surface Heparan Sulfate Proteoglycan Syndecan-2 Induces the Maturation of Dendritic Spines in Rat Hippocampal Neurons , 1999, The Journal of cell biology.

[20]  A. Woods,et al.  Multimerization of the Cytoplasmic Domain of Syndecan-4 Is Required for Its Ability to Activate Protein Kinase C* , 1997, The Journal of Biological Chemistry.

[21]  G. Reekmans,et al.  Syntenin, a PDZ protein that binds syndecan cytoplasmic domains. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A. Woods,et al.  Syndecan-4 Proteoglycan Regulates the Distribution and Activity of Protein Kinase C* , 1997, The Journal of Biological Chemistry.

[23]  M. Bernfield,et al.  Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice , 2000, Nature Genetics.

[24]  H. Saito,et al.  Syndecan-4 Deficiency Impairs Focal Adhesion Formation Only under Restricted Conditions* , 2000, The Journal of Biological Chemistry.

[25]  W. Kolch,et al.  Inhibition of Raf-1 signaling by a monoclonal antibody, which interferes with Raf-1 activation and with Mek substrate binding. , 1996, Oncogene.

[26]  R. Weinberg,et al.  Direct Interaction of CASK/LIN-2 and Syndecan Heparan Sulfate Proteoglycan and Their Overlapping Distribution in Neuronal Synapses , 1998, The Journal of cell biology.

[27]  J. Turnbull,et al.  Cell surface syndecan-1 on distinct cell types differs in fine structure and ligand binding of its heparan sulfate chains. , 1994, The Journal of biological chemistry.

[28]  K. Kent,et al.  Enhancement of migration by protein kinase Calpha and inhibition of proliferation and cell cycle progression by protein kinase Cdelta in capillary endothelial cells. , 1997, The Journal of biological chemistry.

[29]  S. McLaughlin,et al.  Binding of neomycin to phosphatidylinositol 4,5-bisphosphate (PIP2). , 1989, Biochimica et biophysica acta.

[30]  I. Ethell,et al.  Synbindin, a Novel Syndecan-2–Binding Protein in Neuronal Dendritic Spines , 2000, The Journal of cell biology.

[31]  M. Detmar,et al.  Delayed wound repair and impaired angiogenesis in mice lacking syndecan-4. , 2001, The Journal of clinical investigation.

[32]  M. Götte,et al.  Functions of cell surface heparan sulfate proteoglycans. , 1999, Annual review of biochemistry.

[33]  Walter Kolch,et al.  Protein kinase Cα activates RAF-1 by direct phosphorylation , 1993, Nature.

[34]  R. Rosenberg,et al.  Molecular cloning and expression of two distinct cDNA-encoding heparan sulfate proteoglycan core proteins from a rat endothelial cell line. , 1992, The Journal of biological chemistry.

[35]  K. Morgan,et al.  Requirement for Protein Kinase C θ for Cell Cycle Progression and Formation of Actin Stress Fibers and Filopodia in Vascular Endothelial Cells* , 1997, The Journal of Biological Chemistry.

[36]  M. Ferguson,et al.  Smooth muscle cell expression of extracellular matrix genes after arterial injury. , 1994, The American journal of pathology.

[37]  A. Woods,et al.  Syndecan 4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion component. , 1994, Molecular biology of the cell.

[38]  S. Cockcroft,et al.  Type I Phosphatidylinositol 4-Phosphate 5-Kinase Directly Interacts with ADP-ribosylation Factor 1 and Is Responsible for Phosphatidylinositol 4,5-Bisphosphate Synthesis in the Golgi Compartment* , 2000, The Journal of Biological Chemistry.

[39]  A. Luini,et al.  ARF mediates recruitment of PtdIns-4-OH kinase-β and stimulates synthesis of PtdIns(4,5)P2 on the Golgi complex , 1999, Nature Cell Biology.

[40]  M. Simons,et al.  Synectin, syndecan‐4 cytoplasmic domain binding PDZ protein, inhibits cell migration , 2000, Journal of cellular physiology.

[41]  K. Kent,et al.  Enhancement of Migration by Protein Kinase Cα and Inhibition of Proliferation and Cell Cycle Progression by Protein Kinase Cδ in Capillary Endothelial Cells* , 1997, The Journal of Biological Chemistry.

[42]  J. Ware,et al.  Inhibition of Protein Kinase C&agr; Prevents Endothelial Cell Migration and Vascular Tube Formation In Vitro and Myocardial Neovascularization In Vivo , 2002, Circulation research.

[43]  B. Kemp,et al.  Protein kinase C contains a pseudosubstrate prototope in its regulatory domain. , 1987, Science.

[44]  Activation of IkappaB kinase beta by protein kinase C isoforms. , 1999, Molecular and cellular biology.

[45]  B. Olwin,et al.  Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation , 1991, Science.

[46]  G. Cooper,et al.  Role of diacylglycerol-regulated protein kinase C isotypes in growth factor activation of the Raf-1 protein kinase , 1997, Molecular and cellular biology.

[47]  V. Wee Yong,et al.  Involvement of p21Waf1/Cip1 in Protein Kinase C Alpha-Induced Cell Cycle Progression , 2000, Molecular and Cellular Biology.

[48]  M. Simons,et al.  Syndecan-4-mediated signalling. , 2001, Cellular signalling.