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First published online 27 October 2009
doi: 10.1242/jcs.054627

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Distinct roles for Crk adaptor isoforms in actin reorganization induced by extracellular signals

Susumu Antoku^* and Bruce J. Mayer

Raymond and Beverly Sackler Laboratory of Genetics and Molecular Medicine, Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030-3301, USA

Author for correspondence (bmayer{at}neuron.uchc.edu)

Accepted 15 September 2009

Crk family adaptors, consisting of Src homology 2 (SH2) and SH3 protein-binding domains, mediate assembly of protein complexes in signaling. CrkI, an alternately spliced form of Crk, lacks the regulatory phosphorylation site and C-terminal SH3 domain present in CrkII and CrkL. We used gene silencing combined with mutational analysis to probe the role of Crk adaptors in platelet-derived growth-factor receptor β (PDGFβR) signaling. We demonstrate that Crk adaptors are required for formation of focal adhesions, and for PDGF-stimulated remodeling of the actin cytoskeleton and cell migration. Crk-dependent signaling is crucial during the early stages of PDGFβR activation, whereas its termination by Abl family tyrosine kinases is important for turnover of focal adhesions and progression of dorsal-membrane ruffles. CrkII and CrkL preferentially activate the small GTPase Rac1, whereas variants lacking a functional C-terminal SH3 domain, including CrkI, preferentially activate Rap1. Thus, differences in the activity of Crk isoforms, including their effectors and their ability to be downregulated by phosphorylation, are important for coordinating dynamic changes in the actin cytoskeleton in response to extracellular signals.

Key words: SH2 domain, SH3 domain, Focal adhesion dynamics, PDGF, Small GTPase

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