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Integrin and syndecan signalling
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Cell migration during developmental, repair and disease processes is critically dependent on interaction with the extracellular matrix (ECM). Focal adhesions are dynamic sites of contact at the cell-ECM interface that serve as points of integration between the ECM and cytoskeleton and as coordinating nexuses of signalling events. Precise spatiotemporal control of focal adhesion dynamics is essential to permit efficient cell migration, regulating both locomotive cellular traction and the signals that dictate directionality. |
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The cell-surface receptors that mediate cell-ECM adhesion are primarily members of two gene families: the integrins and the syndecans. Nearly all ECM molecules contain binding sites for both types of receptor, and there is strong evidence that a full cell-adhesion response requires engagement of both receptor types. Thus, ligation of both integrin and syndecan receptors is required for focal adhesion formation and directionally persistent migration, and perturbation of both receptor families leads to substantial wound healing defects. Interestingly, syndecans also function as co-receptors for growth factors, morphogens and cytokines, which suggests that they may play an important role in coordinating both matrix-associated and secreted environmental signals. |
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While mechanisms of direct integrin-syndecan crosstalk have not yet been identified, analyses in vitro have demonstrated clear synergy between signalling cascades downstream of the two receptor families. We believe that this synergistic signalling plays a fundamental role in microenvironmental sensing and the regulation of cell migration. |
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We are specifically interested in the mechanisms by which these two receptor families regulate each others function in order to spatially and temporally coordinate focal adhesion dynamics, GTPase activity and cell migration. We have previously shown that syndecan-4 engagement is required to control activation of the small GTPase Rac1 in order to regulate directional cell migration and that p190RhoGAP is at least one of the convergence points downstream of syndecan-4 and α5β1 integrin involved in GTPase regulation. The role of syndecan-4 engagement in precisely coordinating these signalling events is fundamental to the regulation of focal adhesion dynamics and the promotion of efficient cell migration. |
 Syndecan-4 cytoplasmic domain PDB entry 1EJP |
Further reading
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