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J. Biol. Chem., Vol. 280, Issue 5, 3346-3354, February 4, 2005

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Tetraspanin CD82 Attenuates Cellular Morphogenesis through Down-regulating Integrin 6-Mediated Cell Adhesion^*

Bo He, Li Liu, George A. Cook, Svetozar Grgurevich, Lisa K. Jennings, and Xin A. Zhang¶

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

Tetraspanin CD82 has been implicated in integrin-mediated functions such as cell motility and invasiveness. Although tetraspanins associate with integrins, it is unknown if and how CD82 regulates the functionality of integrins. In this study, we found that Du145 prostate cancer cells underwent morphogenesis on the reconstituted basement membrane Matrigel to form an anastomosing network of multicellular structures. This process entirely depends on integrin 6, a receptor for laminin. After CD82 is expressed in Du145 cells, this cellular morphogenesis was abolished, indicating a functional cross-talk between CD82 and 6 integrins. Interestingly, antibodies against other tetraspanins expressed in Du145 cells such as CD9, CD81, and CD151 did not block this integrin 6-dependent morphogenesis. We further found that CD82 significantly inhibited cell adhesion on laminin 1. Notably, the level of 6 integrins on the cell surface was down-regulated upon CD82 expression, although total cellular 6 protein levels remained unchanged in CD82-expressing cells. This down-regulation indicates that the diminished cell adhesiveness of CD82-expressing Du145 cells on laminin likely resulted from less cell surface expression of 6 integrins. As expected, CD82 physically associated with the integrin 6 in Du145-CD82 transfectant cells, suggesting that the formation of the CD82-integrin 6 complex reduces 6 integrin cell surface expression. Finally, the internalization of cell surface integrin 6 is significantly enhanced upon CD82 expression. In conclusion, our results indicate that 1) CD82 attenuates integrin 6 signaling during a cellular morphogenic process; 2) the decreased surface expression of 6 integrins in CD82-expressing cells is likely responsible for the diminished adhesiveness on laminin and, subsequently, results in the attenuation of 6 integrin-mediated cellular morphogenesis; and 3) the accelerated internalization of integrin 6 upon CD82 expression correlates with the down-regulation of cell surface integrin 6.

Received for publication, June 15, 2004 , and in revised form, October 25, 2004.

^* This study was supported by the National Institutes of Health Grant CA-96991 and Army Grant PC030970 (W81XWH-04-1-0156) (to X. A. Z.). 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, 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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