Phosphorylation of Dok1 by Abl family kinases inhibits CrkI transforming activity View Full Text


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Article Info

DATE

2014-07-21

AUTHORS

K Y Ng, T Yin, K Machida, Y I Wu, B J Mayer

ABSTRACT

The Crk SH2/SH3 adaptor and the Abl nonreceptor tyrosine kinase were first identified as oncoproteins, and both can induce tumorigenesis when overexpressed or mutationally activated. We previously reported the surprising finding that inhibition or knockdown of Abl family kinases enhanced transformation of mouse fibroblasts by CrkI. Abl family inhibitors are currently used or are being tested for treatment of human malignancies, and our finding raised concerns that such inhibitors might actually promote the growth of tumors overexpressing CrkI. Here, we identify the Dok1 adaptor as the key effector for the enhancement of CrkI transformation by Abl inhibition. We show that phosphorylation of tyrosines 295 and 361 of Dok1 by Abl family kinases suppresses CrkI transforming activity, and that upon phosphorylation these tyrosines bind the SH2 domains of the Ras inhibitor p120 RasGAP. Knockdown of RasGAP resulted in a similar enhancement of CrkI transformation, consistent with a critical role for Ras activity. Imaging studies using a FRET sensor of Ras activation revealed alterations in the localization of activated Ras in CrkI-transformed cells. Our results support a model in which Dok1 phosphorylation normally suppresses localized Ras pathway activity in Crk-transformed cells via recruitment and/or activation of RasGAP, and that preventing this negative feedback mechanism by inhibiting Abl family kinases leads to enhanced transformation by Crk. More... »

PAGES

2650-2659

References to SciGraph publications

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  • 1988-03. A novel viral oncogene with structural similarity to phospholipase C in NATURE
  • 2004-01-19. Frameshift mutation in the Dok1 gene in chronic lymphocytic leukemia in ONCOGENE
  • 1997-02-06. Tyrosine 207 in CRKL is the BCR/ABL phosphorylation site in ONCOGENE
  • 2010-06-14. Mice lacking Dok-1, Dok-2, and Dok-3 succumb to aggressive histiocytic sarcoma in LABORATORY INVESTIGATION
  • 2003-09-11. Increased C-CRK proto-oncogene expression is associated with an aggressive phenotype in lung adenocarcinomas in ONCOGENE
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/onc.2014.210

    DOI

    http://dx.doi.org/10.1038/onc.2014.210

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1037972605

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/25043303


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