Cytoplasmic interactions of syndecan-4 orchestrate adhesion receptor and growth factor receptor signalling.
Syndecan-4 is a ubiquitous transmembrane proteoglycan that localizes to the focal adhesions of adherent cells and binds to a range of extracellular ligands, including growth factors and extracellular-matrix proteins. Engagement of syndecan-4 is essential for adhesion formation in cells adhering via certain integrins, and for cell proliferation and migration in response to growth factors. The cytoplasmic domain of syndecan-4 interacts with a number of signalling and structural proteins, and both extracellular and cytoplasmic domains are necessary for regulated activation of associated transmembrane receptors. PDZ domain-containing scaffold proteins (syntenin and CASK) bind to the C-terminus of the syndecan-4 cytoplasmic domain and co-ordinate clustering of receptors and connection to the actin cytoskeleton. Syndecan-4 also binds and activates protein kinase Calpha in the presence of phosphatidylinositol 4,5-bisphosphate, and regulates signalling by Rho-family GTPases and focal adhesion kinase. This review discusses the cytoplasmic interactions of syndecan-4 and how they affect cell behaviour as a consequence of the interaction with extracellular ligands. These conclusions also offer an insight into the role of syndecan-4 in vivo, and are consistent with phenotypes generated as a consequence of abnormal syndecan-4 expression in pathologies and gene disruption studies.
Bass
Mark D
MD
Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, Manchester M13 9PT, U.K.
Humphries
Martin J
MJ
D000199:Actins / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D019281:Dimerization; D005109:Extracellular Matrix / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D010766:Phosphorylation; D019038:Platelet Glycoprotein GPIb-IX Complex; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D053671:Syndecan-4; D014945:Wound Healing / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D006497:Heparan Sulfate; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D011509:Proteoglycans; D017978:Receptors, Growth Factor; D053671:Syndecan-4; D020741:rho GTP-Binding Proteins; C508304:SDC4 protein, human; C094990:adhesion receptor