PTK6 regulates IGF-1-induced anchorage-independent survival

Hanna Y. Irie, Yashaswi Shrestha, Laura M. Selfors, Fabianne Frye, Naoko Iida, Zhigang Wang, Lihua Zou, Jun Yao, Yiling Lu, Charles B. Epstein, Sridaran Natesan, Andrea L. Richardson, Kornelia Polyak, Gordon B. Mills, William C. Hahn, Joan S. Brugge

    Research output: Contribution to journalArticlepeer-review

    46 Scopus citations

    Abstract

    Background: Proteins that are required for anchorage-independent survival of tumor cells represent attractive targets for therapeutic intervention since this property is believed to be critical for survival of tumor cells displaced from their natural niches. Anchorage-independent survival is induced by growth factor receptor hyperactivation in many cell types. We aimed to identify molecules that critically regulate IGF-1-induced anchorage-independent survival. Methods and Results: We conducted a high-throughput siRNA screen and identified PTK6 as a critical component of IGF-1 receptor (IGF-1R)-induced anchorage-independent survival of mammary epithelial cells. PTK6 downregulation induces apoptosis of breast and ovarian cancer cells deprived of matrix attachment, whereas its overexpression enhances survival. Reverse-phase protein arrays and subsequent analyses revealed that PTK6 forms a complex with IGF-1R and the adaptor protein IRS-1, and modulates anchorage-independent survival by regulating IGF-1R expression and phosphorylation. PTK6 is highly expressed not only in the previously reported Her2+ breast cancer subtype, but also in high grade ER+, Luminal B tumors and high expression is associated with adverse outcomes. Conclusions: These findings highlight PTK6 as a critical regulator of anchorage-independent survival of breast and ovarian tumor cells via modulation of IGF-1 receptor signaling, thus supporting PTK6 as a potential therapeutic target for multiple tumor types. The combined genomic and proteomic approaches in this report provide an effective strategy for identifying oncogenes and their mechanism of action.

    Original languageEnglish (US)
    Article numbere11729
    JournalPloS one
    Volume5
    Issue number7
    DOIs
    StatePublished - 2010

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)
    • Agricultural and Biological Sciences(all)
    • General

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