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J. Biol. Chem., Vol. 281, Issue 34, 24279-24292, August 25, 2006

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Homophilic Interactions of Tetraspanin CD151 Up-regulate Motility and Matrix Metalloproteinase-9 Expression of Human Melanoma Cells through Adhesion-dependent c-Jun Activation Signaling Pathways^*

In-Kee Hong, Young-June Jin, Hee-Jung Byun, Doo-Il Jeoung, Young-Myeong Kim^¶, and Hansoo Lee¹

From the Vascular System Research Center and Division of Life Sciences, College of Natural Sciences, and ^¶Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chunchon, Kangwon-do 200-701, Korea

The tetraspanin membrane protein CD151 has been suggested to regulate cancer invasion and metastasis by initiating signaling events. The CD151-mediated signaling pathways involved in this regulation remain to be revealed. In this study, we found that stable transfection of CD151 into MelJuSo human melanoma cells lacking CD151 expression significantly increased cell motility, matrix metalloproteinase-9 (MMP-9) expression, and invasiveness. The enhancement of cell motility and MMP-9 expression by CD151 overexpression was abrogated by inhibitors and small interfering RNAs targeted to focal adhesion kinase (FAK), Src, p38 MAPK, and JNK, suggesting an essential role of these signaling components in CD151 signaling pathways. Also, CD151-induced MMP-9 expression was shown to be mediated by c-Jun binding to AP-1 sites in the MMP-9 gene promoter, indicating AP-1 activation by CD151 signaling pathways. Meanwhile, CD151 was found to be associated with ₃₁ and ₆₁ integrins in MelJuSo cells, and activation of associated integrins was a prerequisite for CD151-stimulated MMP-9 expression and activation of FAK, Src, p38 MAPK, JNK, and c-Jun. Furthermore, CD151 on one cell was shown to bind to neighboring cells expressing CD151, suggesting that CD151 is a homophilic interacting protein. The homophilic interactions of CD151 increased motility and MMP-9 expression of CD151-transfected MelJuSo cells, along with FAK-, Src-, p38 MAPK-, and JNK-mediated activation of c-Jun in an adhesion-dependent manner. Furthermore, C8161 melanoma cells with endogenous CD151 were also shown to respond to homophilic CD151 interactions for the induction of adhesion-dependent activation of FAK, Src, and c-Jun. These results suggest that homophilic interactions of CD151 stimulate integrin-dependent signaling to c-Jun through FAK-Src-MAPKs pathways in human melanoma cells, leading to enhanced cell motility and MMP-9 expression.

Received for publication, February 8, 2006 , and in revised form, June 23, 2006.

^* This work was supported by a Vascular System Research grant from the Korean Science and Engineering Foundation. 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.

¹ To whom correspondence should be addressed: Division of Life Sciences, College of Natural Sciences, Kangwon National University, Chunchon, Kangwon-do, 200-701, South Korea. Tel.: 82-33-250-8530; Fax: 82-33-244-3286; E-mail: hslee{at}kangwon.ac.kr.

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