Phosphorylation of Crk on tyrosine 251 in the RT loop of the SH3C domain promotes Abl kinase transactivation View Full Text


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Article Info

DATE

2011-05-23

AUTHORS

G Sriram, C Reichman, A Tunceroglu, N Kaushal, T Saleh, K Machida, B Mayer, Q Ge, J Li, P Hornbeck, C G Kalodimos, R B Birge

ABSTRACT

Here, we report the identification and characterization of a novel tyrosine phosphorylation site in the carboxy-terminal Src Homology 3 (SH3) (SH3C) domain of the Crk adaptor protein. Y251 is located in the highly conserved RT loop structure of the SH3C, a region of Crk involved in the allosteric regulation of the Abl kinase. Exploiting kinase assays to show that Y251 is phosphorylated by Abl in vitro, we generated affinity-purified antisera against phosphorylated Y251 in Crk and showed that Abl induces phosphorylation at Y251 in vivo, and that the kinetics of phosphorylation at Y251 and the negative regulatory Y221 site in vitro are similar. Y251 on endogenous Crk was robustly phosphorylated in chronic myelogenous leukemia cell lines and in A431 and MDA-MB-468 cells stimulated with epidermal growth factor. Using streptavidin–biotin pull downs and unbiased high-throughput Src Homology 2 (SH2) profiling approaches, we found that a pY251 phosphopeptide binds specifically to a subset of SH2 domains, including Abl and Arg SH2, and that binding of pY251 to Abl SH2 induces transactivation of Abl 1b. Finally, the Y251F Crk mutant significantly abrogates Abl transactivation in vitro and in vivo. These studies point to a yet unrealized positive regulatory role resulting from tyrosine phosphorylation of Crk, and identify a novel mechanism by which an adaptor protein activates a non-receptor tyrosine kinase by SH2 domain displacement. More... »

PAGES

4645-4655

References to SciGraph publications

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  • 1995-03. Direct demonstration of an intramolecular SH2—phosphotyrosine interaction in the Crk protein in NATURE
  • 2009-05-10. Crk and CrkL adaptor proteins: networks for physiological and pathological signaling in CELL COMMUNICATION AND SIGNALING
  • 2010-12-05. Structural basis for regulation of the Crk signaling protein by a proline switch in NATURE CHEMICAL BIOLOGY
  • 1988-03. A novel viral oncogene with structural similarity to phospholipase C in NATURE
  • 2001-02-22. Activation of the focal adhesion kinase signaling pathway by structural alterations in the carboxyl-terminal region of c-Crk II in ONCOGENE
  • 1998-05-14. Crk protein binds to PDGF receptor and insulin receptor substrate-1 with different modulating effects on PDGF- and insulin-dependent signaling pathways in ONCOGENE
  • 2007-08-13. Aggressive breast cancer cells are dependent on activated Abl kinases for proliferation, anchorage-independent growth and survival in ONCOGENE
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/onc.2011.170

    DOI

    http://dx.doi.org/10.1038/onc.2011.170

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1003926783

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/21602891


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