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J. Biol. Chem., Vol. 278, Issue 29, 27319-27328, July 18, 2003

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Requirement of the p130^CAS-Crk Coupling for Metastasis Suppressor KAI1/CD82-mediated Inhibition of Cell Migration^*

Xin A. Zhang , Bo He, Bin Zhou and Li Liu

From the Vascular Biology Center and Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163

KAI1/CD82 protein is a member of the tetraspanin superfamily and has been rediscovered as a cancer metastasis suppressor. The mechanism of KAI1/CD82-mediated suppression of cancer metastasis remains to be established. In this study, we found that migration of the metastatic prostate cancer cell line Du145 was substantially inhibited when KAI1/CD82 was expressed. The expression of focal adhesion kinase (FAK) and Lyn, a Src family tyrosine kinase and substrate of FAK, was up-regulated at both RNA and protein levels upon KAI1/CD82 expression. The activation of FAK and Lyn, however, remained unchanged in Du145-KAI1/CD82 cells. As a downstream target of FAK-Lyn signaling, the p130^CAS (Crk-associated substrate) protein was decreased upon the expression of KAI1/CD82. Consequently, less p130^CAS-CrkII complex, which functions as a "molecular switch" in cell motility, was formed in Du145-KAI1/CD82 cells. To confirm that the p130^CAS-CrkII complex is indeed important for the motility inhibition by KAI1/CD82, overexpression of p130^CAS in Du145-KAI1/CD82 cells increased the formation of p130^CAS-CrkII complex and largely reversed the KAI1/CD82-mediated inhibition of cell motility. Taken together, our studies indicate the following: 1) signaling of FAK-Lyn-p130^CAS-CrkII pathway is altered in KAI1/CD82-expressing cells, and 2) p130^CAS-CrkII coupling is required for KAI1/CD82-mediated suppression of cell motility.

Received for publication, March 25, 2003 , and in revised form, April 14, 2003.

^* 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: Vascular Biology Center of Excellence, UTHSC, Coleman H300, 956 Court Ave., Memphis, TN 38163. Tel.: 901-448-3448; Fax: 901-448-7181; E-mail: xazhang{at}utmem.edu.

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