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J. Biol. Chem., Vol. 280, Issue 25, 23516-23522, June 24, 2005

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p130^cas but Not Paxillin Is Essential for Caco-2 Intestinal Epithelial Cell Spreading and Migration on Collagen IV^*

Matthew A. Sanders¶ and Marc D. Basson||

From the Department of Surgery, Wayne State University, Research Service and ^||Surgical Service, John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan 48201-1932

We have previously observed that collagen IV regulates Caco-2 intestinal epithelial cell spreading and migration via Src kinase and stimulates Src-dependent tyrosine phosphorylation of p130^cas. We observed that collagen IV also stimulated Src-dependent phosphorylation of both paxillin Tyr³¹ and paxillin Tyr¹¹⁸. Caco-2 transfection with paxillin or p130^cas siRNAs inhibited expression of these proteins by more than 90% for at least 5 days after transfection. Although p130^cas siRNA inhibited cell spreading on collagen IV by 33%, three different paxillin siRNAs did not inhibit cell spreading. p130^cas siRNA did not affect Src Tyr⁴¹⁶ or Src Tyr⁵²⁷ phosphorylation, FAK Tyr³⁹⁷ phosphorylation, or Src-dependent phosphorylation of FAK Tyr⁹²⁵, suggesting that p130^cas did not inhibit cell spreading by altering FAK or Src activity. Rat p130^cas expression after siRNA knock-out of endogenous human p130^cas in Caco-2 cells reduced cell spreading inhibition by 71%. In contrast, expression of rat p130^cas from which the Src-phosphorylated substrate domain was deleted did not rescue siRNA inhibition of cell spreading. Combined treatment with siRNAs to Crk and CrkL, which bind to the p130^cas substrate domain, inhibited cell spreading by 54%. Both p130^cas siRNA and the combined Crk/CrkL siRNAs strongly inhibited (52 and 46% inhibition, respectively) Caco-2 sheet migration on collagen IV and noticeably inhibited lamellipodial extension, whereas paxillin siRNA only inhibited migration by 18% and did not noticeably affect lamellipodial extension. These results suggest that Src may regulate Caco-2 migration on collagen IV via both p130^cas and paxillin but that Src phosphorylation of p130^cas is more important for this process.

Received for publication, November 22, 2004 , and in revised form, March 18, 2005.

^* This work was supported in part by National Institutes of Health Grant R01DK60771 and a Veterans Affairs Merit Award (to M. D. B.). 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: Research Service, John D. Dingell Veterans Affairs Medical Center, 4646 John R. St., Detroit, MI 48201-1932. Tel.: 313-576-1000 (ext. 4455); E-mail: aj2198{at}wayne.edu.

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