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PLoS One. 2010 Jul 23;5(7):e11729. doi: 10.1371/journal.pone.0011729.

PTK6 regulates IGF-1-induced anchorage-independent survival.

Author information

1
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, United States of America.

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.

PMID:
20668531
PMCID:
PMC2909213
DOI:
10.1371/journal.pone.0011729
[Indexed for MEDLINE]
Free PMC Article

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