Crk at the quarter century mark: Perspectives in signaling and cancer

The Crk adaptor protein, discovered 25 years ago as the transforming gene (v-crk) product encoded by the CT10 avian retrovirus, has made a great impact on the field of signal transduction. By encoding an oncoprotein that contained a viral gag protein fused to only SH2 and SH3 domains, v-Crk demonstrated the significance of SH2 and SH3 domains in oncogenic signaling by their virtue of binding in a sequence-specific context to organize and assemble protein networks. In more recent years, the cellular homologs of Crk (Crk II, Crk I, and CrkL) have been extensively studied, and shown to have critical functions in a wide spectrum of biological and pathological processes that include cell motility, invasion, survival, bacterial pathogenesis, and the efferocytosis of apoptotic cells. Clinically, Crk proteins are implicated in the aggressive behavior of human cancers, including adenocarcinomas of the lung, breast, and stomach, as well as in sarcomas and gliomas. Over-expression of Crk proteins in human cancers has led to a renewed interest in both their signal transduction pathways and mechanisms of up-regulation. This prospect summarizes recent developments in Crk biology, including new structural and biochemical roles for the atypical carboxyl-terminal SH3 (SH3C) domain, revelations regarding the molecular differences between Crk II and Crk L, and the significance of Crk expression in stratified human tumor samples.