Martin Humphries
LAB

Integrin and syndecan signalling



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. (See our Cell-ECM interactions gallery for a selection of images.) 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.


Syndecan mediated coordination of receptor signalling

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.


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.


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

Syndecan-4 cytoplasmic domain

PDB entry 1EJP

Related galleries



Further reading


  • MD Bass, MR Morgan, KA Roach, J Settleman, AB Goryachev and MJ Humphries (2008) p190RhoGAP is the convergence point of adhesion signals from α5β1 integrin and syndecan-4. J. Cell Biol. 181: 1013-26. Full text | PubMed entry


  • MR Morgan, MJ Humphries and MD Bass (2007) Synergistic control of cell adhesion by integrins and syndecans. Nat. Rev. Mol. Cell Biol. 8: 957-69. Full text | PubMed entry


  • MD Bass, KA Roach, MR Morgan, Z Mostafavi-Pour, T Schoen, T Muramatsu, U Mayer, C Ballestrem, JP Spatz and MJ Humphries (2007) Syndecan-4-dependent Rac1 regulation determines directional migration in response to the extracellular matrix. J. Cell Biol. 177: 527-38. Full text | PubMed entry