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Mol Cancer Res. 2018 Jan;16(1):173-183. doi: 10.1158/1541-7786.MCR-17-0242. Epub 2017 Oct 3.

Crk Tyrosine Phosphorylation Regulates PDGF-BB-inducible Src Activation and Breast Tumorigenicity and Metastasis.

Author information

1
Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers New Jersey Medical School, Newark, New Jersey.
2
Protein Quality Control and Diseases Laboratory, Cancer Center, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
3
Cell Signaling Technology, Danvers, Massachusetts.
4
Raymond and Beverly Sackler Laboratory of Genetics and Molecular Medicine, Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, Connecticut.
5
Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers New Jersey Medical School, Newark, New Jersey. birgera@njms.rutgers.edu.

Abstract

The activity of Src family kinases (Src being the prototypical member) is tightly regulated by differential phosphorylation on Tyr416 (positive) and Tyr527 (negative), a duet that reciprocally regulates kinase activity. The latter negative regulation of Src on Tyr527 is mediated by C-terminal Src kinase (CSK) that phosphorylates Tyr527 and maintains Src in a clamped negative regulated state by promoting an intramolecular association. Here it is demonstrated that the SH2- and SH3-domain containing adaptor protein CrkII, by virtue of its phosphorylation on Tyr239, regulates the Csk/Src signaling axis to control Src activation. Once phosphorylated, the motif (PIpYARVIQ) forms a consensus sequence for the SH2 domain of CSK to form a pTyr239-CSK complex. Functionally, when expressed in Crk-/- MEFs or in Crk+/+ HS683 cells, Crk Y239F delayed PDGF-BB-inducible Src Tyr416 phosphorylation. Moreover, expression of Crk Y239F in HS683 cells delayed Src kinase activation and suppressed the cell-invasive and -transforming phenotypes. Finally, through loss-of-function and epistasis experiments using CRISPR-Cas9-engineered 4T1 murine breast cancer cells, Crk Tyr239 is implicated in breast cancer tumor growth and metastasis in orthotopic immunocompetent 4T1 mice model of breast adenocarcinoma. These findings delineate a novel role for Crk Tyr239 phosphorylation in the regulation of Src kinases, as well as a potential molecular explanation for a long-standing question as to how Crk regulates the activation of Src kinases.Implications: These findings provide new perspectives on the versatility of Crk in cancer by demonstrating how Crk mechanistically drives, through a tyrosine phosphorylation-dependent manner, tumor growth, and metastasis. Mol Cancer Res; 16(1); 173-83. ©2017 AACR.

PMID:
28974561
DOI:
10.1158/1541-7786.MCR-17-0242
[Indexed for MEDLINE]
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