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J. Biol. Chem., Vol. 280, Issue 34, 30564-30573, August 26, 2005

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Tumor Cell Pseudopodial Protrusions

LOCALIZED SIGNALING DOMAINS COORDINATING CYTOSKELETON REMODELING, CELL ADHESION, GLYCOLYSIS, RNA TRANSLOCATION, AND PROTEIN TRANSLATION^*

Zongjian Jia, Laurence Barbier, Heather Stuart, Mohammad Amraei, Steven Pelech¶||, James W. Dennis**, Pavel Metalnikov**, Paul O'Donnell**, and Ivan R. Nabi

From the Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, the Department of Pathology and Cell Biology, Université de Montréal, Quebec H3C 3J7, the ^¶Kinexus Bioinformatics Corporation, Vancouver, British Columbia V6T 1Z3, the ^||Department of Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, and the ^**Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario M5G 1X5, Canada

The pseudopodial protrusions of Moloney sarcoma virus (MSV)-Madin-Darby canine kidney (MDCK)-invasive (INV) variant cells were purified on 1-µm pore polycarbonate filters that selectively allow passage of the pseudopodial domains but not the cell body. The purified pseudopodial fraction contains phosphotyrosinated proteins, including Met and FAK, and various signaling proteins, including Raf1, MEK1, ERK2, PKB (Akt1), GSK3, GSK3, Rb, and Stat3. Pseudopodial proteins identified by liquid chromatography tandem mass spectrometry included actin and actin-regulatory proteins (ERM, calpain, filamin, myosin, Sra-1, and IQGAP1), tubulin, vimentin, adhesion proteins (vinculin, talin, and 1 integrin), glycolytic enzymes, proteins associated with protein translation, RNA translocation, and ubiquitin-mediated protein degradation, as well as protein chaperones (HSP90 and HSC70) and signaling proteins (RhoGDI and ROCK). Inhibitors of MEK1 (U0126) and HSP90 (geldanamycin) significantly reduced MSV-MDCK-INV cell motility and pseudopod expression, and geldanamycin treatment inhibited Met phosphorylation and induced the expression of actin stress fibers. ROCK inhibition did not inhibit cell motility but transformed the pseudopodial protrusions of MSV-MDCK-INV cells into extended lamellipodia. Dominant negative Rho disrupted pseudopod expression and, in serum-starved cells, L--lysophosphatidic acid (oleoyl) activation of Rho induced pseudopodial protrusions or, in the presence of the ROCK inhibitor, extended lamellipodia. RNA was localized to the actin-rich pseudopodial domains of MSV-MDCK-INV cells, but the extent of colocalization with dense actin ruffles was reduced in the extended lamellipodia formed upon ROCK inhibition. Rho/ROCK activation in epithelial tumor cells therefore regulates RNA translocation to a pseudopodial domain that contains proteins involved in signaling, cytoskeleton remodeling, cell adhesion, glycolysis, and protein translation and degradation.

Received for publication, February 15, 2005 , and in revised form, June 28, 2005.

^* This work was supported in part by a grant from the Cancer Research Society Inc. (to I. R. N.). 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.

Recipient of a Canadian Institutes for Health Research Investigator award. To whom correspondence should be addressed: Dept. of Cellular and Physiological Sciences, University of British Columbia, 2177 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada. Tel.: 604-822-7000; Fax: 604-822-2316; E-mail: irnabi{at}interchange.ubc.ca.

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