Apoptotic Regulation by the Crk Adapter Protein Mediated by Interactions with Wee1 and Crm1/Exportin

Abstract

The adapter protein Crk contains an SH2 domain and two SH3 domains. Through binding of particular ligands to the SH2 domain and the N-terminal SH3 domain, Crk has been implicated in a number of signaling processes, including regulation of cell growth, cell motility, and apoptosis. We report here that the C-terminal SH3 domain, never shown to bind any specific signaling molecules, contains a binding site for the nuclear export factor Crm1. We find that a mutant Crk protein, deficient in Crm1 binding, promotes apoptosis. Moreover, this nuclear export sequence mutant [NES(−) Crk] interacts strongly, through its SH2 domain, with the nuclear tyrosine kinase, Wee1. Collectively, these data suggest that a nuclear population of Crk bound to Wee1 promotes apoptotic death of mammalian cells.

We thank Gerard Grosveld for anti-Crm1 antibodies, Helen Piwnica-Worms for the human Wee1 clone, and Bruce Mayer for anti-Crk sera and wild-type Crk II clone. We thank Robert Abraham and Danny Lew for critical comments on the manuscript.

This work was supported by an NIH grant to S.K. (RO1 GM56518) and by the Breast Cancer Research Program of the USARMC. S.K. is a Scholar of the Leukemia and Lymphoma Society.