Synergistic control of cell adhesion by integrins and syndecans

Abstract

Integrins and syndecans are two families of transmembrane matrix receptors that cooperate during cell adhesion to support focal-adhesion formation. The cytoplasmic domain of syndecan-4 includes a unique motif that activates protein kinase Cα (PKCα) by direct association. The link from syndecan-4 to PKCα has the potential to regulate integrin activation, in addition to regulating signals downstream of both receptors. Syndecan-4 regulates both Rac1 and RhoA GTPases through PKCα and, in the case of Rac1, is essential for adhesion-dependent activation. Adhesion-dependent regulation of GTPases has been linked to the determination of directional cell migration. Disruption of either syndecan-1 or syndecan-4 genes compromises wound healing in adult animals without causing any apparent developmental defects. This phenotype suggests that syndecans have specialized roles that are dependent on the ability of cells to migrate efficiently in response to a matrix stimulus. α_Vβ₃ integrin, α_Vβ₅ integrin and α₅β₁ integrin have crucial roles in the regulation of pathological angiogenesis. The authors propose that syndecans-1 and -4 have the potential to regulate angiogenesis through their synergistic relationships with these integrins and through heparan-sulphate-dependent regulation of growth-factor localization. Transgenic mice that are deficient for syndecan-3 or various β₁ integrin heterodimers exhibit defects in neuronal migration. In Drosophila melanogaster, both integrins and syndecan regulate axonal guidance through differential regulation of the Slit–Robo system. The molecular mechanisms underlying integrin–syndecan synergy are becoming increasingly clear, and it is apparent that this is required for efficient directional migration. Accumulating in vivo data suggest that integrin–syndecan synergy might regulate biological processes that rely on the precisely coordinated regulation of directional migration.