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J. Biol. Chem., Vol. 278, Issue 25, 22374-22378, June 20, 2003
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From the
British Columbia Cancer Agency and Department of Biochemistry, University of British Columbia, Jack Bell Research Centre, Vancouver, British Columbia V6H 3Z6, Canada, ¶The Prostate Centre, Vancouver Hospital Health Sciences Centre and Department of Surgery, University of British Columbia, Vancouver, British Columbia V6H 3Z5, Canada, and ||Shriners Hospital and McGill University, Montréal, Québec H3G 1A6, Canada
Protein kinase B (PKB/Akt) plays a pivotal role in signaling pathways downstream of phosphatidylinositol 3-kinase, regulating fundamental processes such as cell survival, cell proliferation, differentiation, and metabolism. PKB/Akt activation is regulated by phosphoinositide phospholipid-mediated plasma membrane anchoring and by phosphorylation on Thr-308 and Ser-473. Whereas the Thr-308 site is phosphorylated by PDK-1, the identity of the Ser-473 kinase has remained unclear and controversial. The integrin-linked kinase (ILK) is a potential regulator of phosphorylation of PKB/Akt on Ser-473. Utilizing double-stranded RNA interference (siRNA) as well as conditional knock-out of ILK using the Cre-Lox system, we now demonstrate that ILK is essential for the regulation of PKB/Akt activity. ILK knock-out had no effect on phosphorylation of PKB/Akt on Thr-308 but resulted in almost complete inhibition of phosphorylation on Ser-473 and significant inhibition of PKB/Akt activity, accompanied by significant stimulation of apoptosis. The inhibition of PKB/Akt Ser-473 phosphorylation was rescued by kinase-active ILK but not by a kinase-deficient mutant of ILK, suggesting a role for the kinase activity of ILK in the stimulation of PKB/Akt phosphorylation. ILK knock-out also resulted in the suppression of phosphorylation of GSK-3
on Ser-9 and cyclin D1 expression. These data establish ILK as an essential upstream regulator of PKB/Akt activation.
Received for publication, March 25, 2003 , and in revised form, April 8, 2003.
* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Supported by a post-doctoral fellowship from the Canadian Institutes of Health Research (CIHR).
** Supported by grants from the Shriners Hospital Foundation and CIHR.
Supported by grants from the National Cancer Institute of Canada (NCIC) through funds raised by the Terry Fox Foundation. Distinguished Scholar of the Michael Smith Foundation for Health Research (MSFHR). To whom correspondence should be addressed: Jack Bell Research Centre, 2660 Oak St., Vancouver, British Columbia V6H 3Z6, Canada. Tel.: 604-875-5655; Fax: 604-875-5452; E-mail: sdedhar{at}interchange.ubc.ca.
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