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J. Biol. Chem., Vol. 280, Issue 28, 26630-26639, July 15, 2005

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Role of Integrin-linked Kinase in Regulating Phosphorylation of Akt and Fibroblast Survival in Type I Collagen Matrices through a 1 Integrin Viability Signaling Pathway^*

Richard Seonghun Nho, Hong Xia, Judy Kahm, Jill Kleidon, Deanna Diebold, and Craig A. Henke

From the Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455

A 1 integrin phosphatidylinositol 3-kinase/Akt pathway regulates fibroblast survival in collagen matrices. When fibroblasts attach to collagen, Akt becomes phosphorylated, providing a survival signal. In contrast, in response to mechanical forces generated during collagen contraction, Akt is dephosphorylated and fibroblasts undergo apoptosis. The kinase(s) responsible for regulating Akt phosphorylation in response to matrix-derived mechanical signals are unclear. Integrin-linked kinase (ILK) is associated with the 1 integrin in the focal adhesion complex and as such is a candidate kinase that may regulate Akt phosphorylation and fibroblast viability. Nevertheless, there is no direct evidence that matrix-derived mechanical forces regulate cell viability by modulating ILK activity. Here, we show that ILK activity decreased in response to collagen matrix contraction, which correlated with Akt dephosphorylation and induction of fibroblast apoptosis. In contrast, enforced activation of 1 integrin by activating antibody preserved ILK and Akt activity during collagen matrix contraction, and this is associated with protection from collagen contraction-induced apoptosis. Knock-down of ILK by small, interfering RNA (siRNA) attenuated Akt phosphorylation in response to ligation of 1 integrin by collagen or activating antibody and enhanced fibroblast apoptosis in response to collagen contraction. Kinase dead ILK attenuated Akt phosphorylation and enhanced fibroblast apoptosis, whereas hyperactive and wild type ILK augmented Akt phosphorylation and protected fibroblasts from apoptosis. Constitutively active Akt preserved Akt activity and rescued ILK siRNA-treated fibroblasts from collagen contraction-induced apoptosis. These data establish that matrix-derived mechanical forces sensed by 1 integrin are capable of modulating ILK activity which regulates fibroblast viability via an Akt-dependent mechanism.

Received for publication, October 18, 2004 , and in revised form, March 25, 2005.

^* 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.

To whom correspondence should be addressed: Box 276, University of Minnesota, 420 Delaware St. S.E., Minneapolis, MN 55455. Tel.: 612-624-0999; Fax: 612-625-2174; E-mail: henke002{at}umn.edu.

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