Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR

X. Li, Y. Lu, K. Liang, J. M. Hsu, C. Albarracin, G. B. Mills, M. C. Hung, Z. Fan

    Research output: Contribution to journalArticle

    33 Scopus citations

    Abstract

    Epidermal growth factor receptor (EGFR)-mediated cell signaling is critical for mammary epithelial cell growth and survival; however, targeting EGFR has shown no or only minimal therapeutic benefit in patients with breast cancer. Here, we report a novel regulatory mechanism of EGFR signaling that may explain the low response rates. We found that breast tumor kinase (Brk)/protein-tyrosine kinase 6 (PTK6), a nonreceptor protein-tyrosine kinase highly expressed in most human breast tumors, interacted with EGFR and sustained ligand-induced EGFR signaling. We demonstrate that Brk inhibits ligand-induced EGFR degradation through uncoupling activated EGFR from casitas B-lineage lymphoma-mediated EGFR ubiquitination. In addition, upon activation by EGFR, Brk directly phosphorylated Y845 in the EGFR kinase domain, thereby further potentiating EGFR kinase activity. Experimental elevation of Brk conferred resistance of breast cancer cells to cetuximab (an EGFR-blocking antibody)-induced inhibition of cell signaling and proliferation, whereas knockdown of Brk sensitized the cells to cetuximab by inducing apoptosis. Our findings reveal a previously unknown role of Brk in EGFR-targeted therapy.

    Original languageEnglish (US)
    Pages (from-to)4372-4383
    Number of pages12
    JournalOncogene
    Volume31
    Issue number40
    DOIs
    StatePublished - Oct 4 2012

    Keywords

    • Brk
    • Cbl
    • EGFR
    • Src
    • breast cancer

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

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  • Cite this

    Li, X., Lu, Y., Liang, K., Hsu, J. M., Albarracin, C., Mills, G. B., Hung, M. C., & Fan, Z. (2012). Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR. Oncogene, 31(40), 4372-4383. https://doi.org/10.1038/onc.2011.608