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J. Biol. Chem., Vol. 280, Issue 28, 26278-26286, July 15, 2005

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Binding of Activated ₂-Macroglobulin to Its Cell Surface Receptor GRP78 in 1-LN Prostate Cancer Cells Regulates PAK-2-dependent Activation of LIMK^*

Uma Kant Misra, Rohit Deedwania, and Salvatore Vincent Pizzo

From the Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710

Two characteristics of highly malignant cells are their increased motility and secretion of proteinases allowing these cells to penetrate surrounding basement membranes and metastasize. Activation of 21-kDa activated kinases (PAKs) is an important mechanism for increasing cell motility. Recently, we reported that binding of receptor-recognized forms of the proteinase inhibitor ₂-macroglobulin (₂M*) to GRP78 on the cell surface of 1-LN human prostate cancer cells induces mitogenic signaling and cellular proliferation. In the current study, we have examined the ability of ₂M* to activate PAK-1 and PAK-2. Exposure of 1-LN cells to ₂M* caused a 2- to 3-fold increase in phosphorylated PAK-2 and a similar increase in its kinase activity toward myelin basic protein. By contrast, the phosphorylation of PAK-1 was only negligibly affected. Silencing the expression of the GRP78 gene, using either of two different mRNA sequences, greatly attenuated the appearance of phosphorylated PAK-2 in ₂M*-stimulated cells. Treatment of 1-LN cells with ₂M* caused translocation of PAK-2 in association with NCK to the cell surface as evidenced by the coimmunoprecipitation of PAK-2 and NCK in the GRP78 immunoprecipitate from plasma membranes. ₂M*-induced activation of PAK-2 was inhibited by prior incubation of the cells with specific inhibitors of tyrosine kinases and phosphatidylinositol 3-kinase. PAK-2 activation was accompanied by significant increases in the levels of phosphorylated LIMK and phosphorylated cofilin. Silencing the expression of the PAK-2 gene greatly attenuated the phosphorylation of LIMK. In conclusion, we show for the first time the activation of PAK-2 in 1-LN prostate cancer cells by a proteinase inhibitor, ₂-macroglobulin. These studies suggest a mechanism by which ₂M* enhances the metastatic potential of these cells.

Received for publication, December 22, 2004 , and in revised form, April 12, 2005.

^* This work was supported by Grant HL-24066 from the NHLBI, National Institutes of Health. 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: Dept. of Pathology, Duke University Medical Center, Dept. of Pathology, Box 3712, Durham, NC 27710. Tel.: 919-684-3528; Fax: 919-684-8689; E-mail: Pizzo001{at}mc.duke.edu.

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