Fan, G., Lin, G., Lucito, R., Tonks, N. K. (June 2013) Protein Tyrosine Phosphatase 1B Antagonized Signaling by IGF-1 Receptor and BRK/PTK6 in Ovarian Cancer Cells. Journal of Biological Chemistry, 288 (34). pp. 24923-29434. ISSN 0021-9258
Abstract
Ovarian cancer, which is the leading cause of death from gynecological malignancies, is a heterogeneous disease known to be associated with disruption of multiple signaling pathways. Nevertheless, little is known regarding the role of protein phosphatases in the signaling events that underlie the disease; such knowledge will be essential to gain a complete understanding of the etiology of the disease and how to treat it. We have demonstrated that protein tyrosine phosphatase 1B (PTP1B) was under-expressed in a panel of ovarian carcinoma-derived cell lines, compared to immortalized human ovarian surface epithelial (HOSE) cell lines. Stable restoration of PTP1B in those cancer cell lines substantially decreased cell proliferation, migration and invasion, as well anchorage- independent survival. Mechanistically, the pro-survival IGF-1R signaling pathway was attenuated upon ectopic expression of PTP1B. This was due to dephosphorylation by PTP1B of IGF-1R beta-subunit and BRK/PTK6, a SRC-like protein tyrosine kinase that physically and functionally interacts with IGF-1R beta-subunit. Restoration of PTP1B expression led to enhanced activation of BAD, one of the major pro-death members of BCL-2 family, which triggered cell death through apoptosis. Conversely, inhibition of PTP1B with a small molecular inhibitor, MSI-1436, increased proliferation and migration of immortalized HOSE cell lines. These data reveal an important role for PTP1B as a negative regulator of BRK and IGF-1Rbeta signaling in ovarian cancer cells.
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