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. 2010 Nov;1(11):1132-9.
doi: 10.1177/1947601910397188.

Emerging Roles for Crk in Human Cancer

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Free PMC article

Emerging Roles for Crk in Human Cancer

Ganapathy Sriram et al. Genes Cancer. .
Free PMC article

Abstract

Adaptor proteins are named for their function in assembling complexes of cellular proteins to execute and facilitate transmission of signals. The Crk family of adaptors consists of 2 members, Crk and CrkL. Crk, which was originally isolated as an oncogene, v-Crk, that transforms CEFs, has at least 2 splice variants, CrkI and CrkII, with differing biological activities. All Crk family proteins serve to act as molecular bridges between tyrosine kinases and their substrates and also modulate the specificity and stoichiometry of signaling processes. Signaling via CrkII and CrkL can be negatively regulated via tyrosine phosphorylation-mediated autoinhibition, while such a mechanism is not known to exist for CrkI. Although v-Crk clearly functions as a bona fide oncogene, in recent years, an emerging body of evidence suggests that cellular Crk proteins are overexpressed in human tumors and the expression levels correlate with aggressive and malignant behavior of cancer cells. These properties of Crk proteins make them potential cancer prognosis markers and therapeutic targets.

Keywords: Crk adaptor proteins; cell motility; human cancer; malignant phenotype.

Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the authorship and/or publication of this article.

Figures

Figure 1.
Figure 1.
Schematic of the Crk family of adaptor proteins. Common protein interacting domains of the Crk proteins are indicated in comparison with Src. Gag refers to the group-specific antigen encoded by the CT10 avian retrovirus. Y527 in Src, Y221 in CrkII, and Y207 in CrkL are regulatory tyrosine motifs that bind intramolecularly to the SH2 domain.
Figure 2.
Figure 2.
Feedback regulation of Crk and signaling pathways activated in malignant cells. Crk is engaged in multiple signaling pathways that drive the malignant behavior of cells. Tyrosine-phosphorylated p130cas (via integrins) and Gab1 (via Met receptor) act as molecular switches to assemble complexes of Crk with DOCK180, C3G, or Sos to stimulate indicated phenotypic outcomes. Elevation in Crk expression can also feedback and activate FAK and Src to further increase phosphorylation of p130cas in an amplification loop. Binding of Crk to tyrosine-phosphorylated Gab1 sustains phosphorylation on Y307 to possibly amplify downstream signaling. Activation of Src inhibits miR-126 defining another amplification loop. Finally, activation of Abl from upstream pathways including the engagement of Eph receptors can disassemble signaling complexes by inducing Crk phosphorylation on Y221. Similar pathways may operate for CrkL.

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