Crk Family Adaptors-signalling Complex Formation and Biological Roles

Crk family adaptors are widely expressed and mediate the timely formation of signal transduction protein complexes upon a variety of extracellular stimuli, including various growth and differentiation factors. Selective formation of multi-protein complexes by the Crk and Crk-like (CRKL) proteins depends on specific motifs recognized by their SH2 and SH3 domains. In the case of the first SH3 domains [SH3(1)] a P-x-x-P-x-K motif is crucial for highly selective binding, while the SH2 domains prefer motifs which conform to the consensus pY-x-x-P. Crk family proteins are involved in the relocalization and activation of several different effector proteins which include guanine nucleotide releasing proteins like C3G, protein kinases of the Abl- and GCK-families and small GTPases like Rap1 and Rac. Crk-type proteins have been found not only in vertebrates but also in flies and nematodes. Major insight into the function of Crk within organisms came from the genetic model organism C. elegans, where the Crk-homologue CED-2 regulates cell engulfment and phagocytosis. Other biological outcomes of the Crk-activated signal transduction cascades include the modulation of cell adhesion, cell migration and immune cell responses. Crk family adaptors also appear to play a role in mediating the action of human oncogenes like the leukaemia-inducing Bcr-Abl protein. This review summarizes some key findings and highlights recent insights and open questions.