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Departments of 1 Cancer Genetics and 2 Advanced Therapeutics, BC Cancer Research Centre, British Columbia Cancer Agency; and 3 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada
Requests for reprints: Shoukat Dedhar, BC Cancer Research Centre, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver BC, Canada V5Z 1L3. Phone: 604-675-8029; Fax: 604-675-8184; E-mail: sdedhar{at}interchange.ubc.ca.
Key Words: cancer cell Integrin-Linked Kinase signal transduction
An unbiased proteomic screen to identify integrin-linked kinase (ILK) interactors revealed rictor as an ILK-binding protein. This finding was interesting because rictor, originally identified as a regulator of cytoskeletal dynamics, is also a component of mammalian target of rapamycin complex 2 (mTORC2), a complex implicated in Akt phosphorylation. These functions overlap with known ILK functions. Coimmunoprecipitation analyses confirmed this interaction, and ILK and rictor colocalized in membrane ruffles and leading edges of cancer cells. Yeast two-hybrid assays showed a direct interaction between the NH2- and COOH-terminal domains of rictor and the ILK kinase domain. Depletion of ILK and rictor in breast and prostate cancer cell lines resulted in inhibition of Akt Ser473 phosphorylation and induction of apoptosis, whereas, in several cell lines, depletion of mTOR increased Akt phosphorylation. Akt and Ser473P-Akt were detected in ILK immunoprecipitates and small interfering RNA–mediated depletion of rictor, but not mTOR, inhibited the amount of Ser473P-Akt in the ILK complex. Expression of the NH2-terminal (1–398 amino acids) rictor domain also resulted in the inhibition of ILK-associated Akt Ser473 phosphorylation. These data show that rictor regulates the ability of ILK to promote Akt phosphorylation and cancer cell survival. [Cancer Res 2008;68(6):1618–24]
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