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"Non-Canonical Signaling by the Crk oncogene"

by
Ganapathy Sriram
Biochemistry and Molecular Biology Program
B.E. 2007, PES Institute of Technology (Visvesvaraya Technological University), Bangalore, India


Thesis Advisor: Raymond B. Birge, Ph.D.
Professor
Department of Biochemistry and Molecular Biology

Friday, February 14, 2014
11:00 A.M., MSB E-609b


Abstract

The Crk adaptor protein is a prototypical member of a family of modular SH2 and SH3 domain containing proteins that assemble protein-protein complexes downstream of tyrosine kinases. The coordinated assembly of signaling complexes by the SH2 and N-terminal SH3 (SH3N) domains of Crk has critical roles in cell adhesion, motility, and efferocytosis of apoptotic cells. However, the role of the atypical C-terminal SH3 domain (SH3C) of Crk is unclear. Phosphorylation at Y221 in the linker between the SH3N and SH3C auto-inhibits the SH2 domain by formation of an intramolecular SH2-pY221 auto-clamp to inhibit SH2-SH3N signaling. In the work described in this thesis, we show that concomitantly with Y221, the Crk SH3C is routinely phosphorylated on Y239 and/or Y251, by several extracellular stimuli known to engage Crk. While phosphorylation at Y221 auto-inhibits the Crk SH2, concomitant phosphorylation at Y239/Y251 on the SH3C generates a non-canonical phosphoSH3C-SH3N modular duet in which the SH3N is accessible to PPII ligands. Moreover, the phosphorylated SH3C engages specific non-receptor tyrosine kinases in breast cancer cells via the phosphorylated Y239/Y251 motifs. Finally, in breast cancer cells where Crk is dually phosphorylated at Y221 and Y251 downstream of EGFR, the phosphorylated SH3C promotes cell motility towards EGF in an Abl kinase dependent manner. These studies describe a versatile mechanism wherein phosphorylation of Crk at Y221 is not an off switch but redirects signaling from the SH2-SH3N axis to a phosphoSH3C-SH3N axis, with the SH3N as a common denominator.


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