Phosphorylation of ETS1 by src family kinases prevents its recognition by the COP1 tumor suppressor

Gang Lu, Qing Zhang, Ying Huang, Jiaxi Song, Ross Tomaino, Tobias Ehrenberger, Elgene Lim, Wenbin Liu, Roderick T. Bronson, Michaela Bowden, Jane Brock, Ian E. Krop, Deborah A. Dillon, Steven P. Gygi, Gordon B. Mills, Andrea L. Richardson, Sabina Signoretti, Michael B. Yaffe, William G. Kaelin

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    38 Scopus citations

    Abstract

    Oncoproteins and tumor suppressors antagonistically converge on critical nodes governing neoplastic growth, invasion, and metastasis. We discovered that phosphorylation of the ETS1 and ETS2 transcriptional oncoproteins at specific serine or threonine residues creates binding sites for the COP1 tumor suppressor protein, which is an ubiquitin ligase component, leading to their destruction. In the case of ETS1, however, phosphorylation of a neighboring tyrosine residue by Src family kinases disrupts COP1 binding, thereby stabilizing ETS1. Src-dependent accumulation of ETS1 in breast cancer cells promotes anchorage-independent growth invitro and tumor growth invivo. These findings expand the list of potential COP1 substrates to include proteins whose COP1-binding sites are subject to regulatory phosphorylation and provide insights into transformation by Src family kinases.

    Original languageEnglish (US)
    Pages (from-to)222-234
    Number of pages13
    JournalCancer Cell
    Volume26
    Issue number2
    DOIs
    StatePublished - Aug 11 2014

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    ASJC Scopus subject areas

    • Oncology
    • Cell Biology
    • Cancer Research

    Cite this

    Lu, G., Zhang, Q., Huang, Y., Song, J., Tomaino, R., Ehrenberger, T., Lim, E., Liu, W., Bronson, R. T., Bowden, M., Brock, J., Krop, I. E., Dillon, D. A., Gygi, S. P., Mills, G. B., Richardson, A. L., Signoretti, S., Yaffe, M. B., & Kaelin, W. G. (2014). Phosphorylation of ETS1 by src family kinases prevents its recognition by the COP1 tumor suppressor. Cancer Cell, 26(2), 222-234. https://doi.org/10.1016/j.ccr.2014.06.026