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J. Biol. Chem., Vol. 279, Issue 40, 41695-41705, October 1, 2004

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Distinct Roles of Two Structurally Closely Related Focal Adhesion Proteins, -Parvins and -Parvins, in Regulation of Cell Morphology and Survival^*

Yongjun Zhang, Ka Chen, Yizeng Tu, and Chuanyue Wu

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

Proteins at cell-extracellular matrix adhesions (e.g. focal adhesions) are crucially involved in regulation of cell morphology and survival. We show here that CH-ILKBP/actopaxin/-parvin and affixin/-parvin (abbreviated as - and -parvin, respectively), two structurally closely related integrin-linked kinase (ILK)-binding focal adhesion proteins, are co-expressed in human cells. Depletion of -parvin dramatically increased the level of -parvin, suggesting that -parvin is negatively regulated by -parvin in human cells. Loss of PINCH-1 or ILK, to which - and -parvin bind, significantly reduced the activation of Rac, a key signaling event that controls lamellipodium formation and cell spreading. We were surprised to find that loss of -parvin, but not that of -parvin, markedly stimulated Rac activation and enhanced lamellipodium formation. Overexpression of -parvin, however, was insufficient for stimulation of Rac activation or lamellipodium formation, although it was sufficient for promotion of apoptosis, another important cellular process that is regulated by PINCH-1, ILK, and -parvin. In addition, we show that the interactions of ILK with - and -parvin are mutually exclusive. Overexpression of -parvin or its CH₂ fragment, but not a CH₂ deletion mutant, inhibited the ILK--parvin complex formation. Finally, we provide evidence suggesting that inhibition of the ILK--parvin complex is sufficient, although not necessary, for promotion of apoptosis. These results identify Rac as a downstream target of PINCH-1, ILK, and parvin. Furthermore, they demonstrate that - and -parvins play distinct roles in mammalian cells and suggest that the formation of the ILK--parvin complex is crucial for protection of cells from apoptosis.

Received for publication, February 12, 2004 , and in revised form, June 30, 2004.

^* This work was supported in part by National Institutes of Health Grant GM65188 (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.

To whom correspondence should be addressed: 707B Scaife Hall, Department 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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