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J. Biol. Chem., Vol. 278, Issue 51, 51324-51333, December 19, 2003

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PINCH-1 Is an Obligate Partner of Integrin-linked Kinase (ILK) Functioning in Cell Shape Modulation, Motility, and Survival^*

Tomohiko Fukuda, Ka Chen, Xiaohua Shi, and Chuanyue Wu

From the Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

PINCH-1 is a widely expressed focal adhesion protein that forms a ternary complex with integrin-linked kinase (ILK) and CH-ILKBP/actopaxin/-parvin (abbreviated as -parvin herein). We have used RNA interference, a powerful approach of reverse genetics, to investigate the functions of PINCH-1 and ILK in human cells. We report here the following. First, PINCH-1 and ILK, but not -parvin, are essential for prompt cell spreading and motility. Second, PINCH-1 and ILK, like -parvin, are crucial for cell survival. Third, PINCH-1 and ILK are required for optimal activating phosphorylation of PKB/Akt, an important signaling intermediate of the survival pathway. Whereas depletion of ILK reduced Ser⁴⁷³ phosphorylation but not Thr³⁰⁸ phosphorylation of PKB/Akt, depletion of PINCH-1 reduced both the Ser⁴⁷³ and Thr³⁰⁸ phosphorylation of PKB/Akt. Fourth, PINCH-1 and ILK function in the survival pathway not only upstream but also downstream (or in parallel) of protein kinase B (PKB)/Akt. Fifth, PINCH-1, ILK and to a less extent -parvin are mutually dependent in maintenance of their protein, but not mRNA, levels. The coordinated down-regulation of PINCH-1, ILK, and -parvin proteins is mediated at least in part by proteasomes. Finally, increased expression of PINCH-2, an ILK-binding protein that is structurally related to PINCH-1, prevented the down-regulation of ILK and -parvin induced by the loss of PINCH-1 but failed to restore the survival signaling or cell shape modulation. These results provide new insights into the functions of PINCH proteins in regulation of ILK and -parvin and control of cell behavior.

Received for publication, August 18, 2003

^* This work was supported by National Institutes of Health Grants GM65188 and DK54639 (to C. W.). 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: 707B Scaife Hall, Dept. of Pathology, University of Pittsburgh, 3550 Terrace St., Pittsburgh, PA 15261. Tel.: 412-648-2350; Fax: 509-561-4062; E-mail: carywu{at}pitt.edu.

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