Trends in Biochemical Sciences
ReviewSignaling networks linking integrins and Rho family GTPases
Section snippets
Integrin regulation of Rho family GTPases
Early studies reported that cells plated on ECM proteins rapidly developed extended filopodia and lamellipodia, indicative of Cdc42 and Rac activity, respectively (reviewed in Ref. 5; Fig. 1). These protrusive structures contain focal complexes, which are localized clusters of integrins, and cytoskeletal and signaling proteins that are smaller than, but similar in composition to, focal adhesions and are characteristically found in contact with the ECM. As cells spread, larger integrin-based
Mechanisms of regulation of Rho family GTPases by integrins
The endogenous GEFs or GAPs that control activation of GTPases by integrins are unknown; indeed, the major Rac and Cdc42 GEFs present in commonly used cell lines have not been identified. However, the proto-oncogene Vav1, a Rac GEF expressed in hematopoietic cells, has been implicated in integrin signaling. Vav1 is regulated in part by phosphorylation on tyrosine residues, which stimulates its GEF activity19. Integrin-mediated adhesion increases tyrosine phosphorylation of Vav1 in several cell
Regulation of integrins by Rho GTPases
Given that Rho GTPases are activated by a variety of extracellular stimuli, and integrin-mediated adhesion can be regulated by some of the same stimuli28, one could hypothesize that Rho GTPases and their effectors regulate the adhesive function of integrins. This idea is supported by several studies in which cells were treated with botulinum C3 exoenzyme, which ADP-ribosylates and inactivates Rho. Integrin-mediated functions blocked by C3 include platelet aggregation (mediated by integrin α
Signaling networks linking integrins and Rho family GTPases
If integrins can activate GTPases or promote their coupling to effectors, while active GTPases can promote integrin-mediated adhesion and signaling, some interesting functional relationships become possible. First, it is suggested that activation of Cdc42 or Rac, or both, is among the earliest events in cell adhesion (Fig. 1). This idea is based on a large body of work indicating that plating of cells on ECM proteins triggers a complex cascade of morphological and biochemical events, some of
Conclusions
Integrin and Rho family GTPase functions are closely intertwined. Both gene families contribute to the regulation of cell growth, gene expression, cytoskeletal organization and cell migration. Recent work has clearly shown that integrins and Rho GTPases regulate each other’s activities. Thus, integrin-triggered signals can regulate both GTPase activation and coupling of active GTPases to their effectors. Reciprocally, Rho GTPases might regulate integrin avidity or post ligand-binding events
Acknowledgements
Work from the authors’ laboratories cited in this article was supported by grants from the National Institutes of Health (GM47214, HL56595, HL57900 and HL48728).
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