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Integrin vß3 mediates K1735 murine melanoma cell motility in vivo and in vitro

Xiaowu Li¹, Joseph Regezi¹, F. Patrick Ross³, Scott Blystone⁴, Duko Ili¹, Stanley P. L. Leong² and Daniel M. Ramos^1,*

¹ Department of Stomatology, University of California San Francisco, San Francisco, CA 94143, USA
² Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA
³ Department of Pathology, Washington University School of Medicine, St Louis, MO 63110, USA
⁴ Departments of Anatomy and Cell Biology, SUNY Health Science Center, Syracuse, NY 13210, USA
^* Author for correspondence (e-mail: dramos{at}itsa.ucsf.edu )

The integrin vß3 has been shown to be tightly linked to progression of human melanoma. In this study, using two clones from the K1735 murine melanoma system, we investigated the role of vß3 in metastasis. The highly metastatic K1735M2 cells express the vß3 integrin, whereas the poorly metastatic K1735C23 cells do not. When transduced with the ß3 integrin subunit cDNA, the K1735C23 cells produced lung lesions and, in two animals, cardiac metastases, whereas the parental C23 cells did not. By contrast, transduction of the full-length ß3 integrin antisense DNA into the K1735M2 cells suppressed metastatic colonization. To specifically investigate the activation of ß3 integrin-mediated pathways, the ß3-positive and the ß3-negative K1735 cells were plated onto vitronectin, a major matrix molecule of both primary and metastatic melanomas. Tyr³⁹⁷ of FAK was phosphorylated several times higher in ß3-expressing K1735 melanoma cells than in ß3-negative cells. To determine whether phosphorylation of FAK was associated with K1735 melanoma motility, we expressed the FAK-related non-kinase (FRNK) in the highly metastatic K1735M2 cells. Exogenous expression of FRNK suppressed phosphorylation of FAK at Tyr³⁹⁷ and decreased the invasive ability of these cells. In addition, expression of a constitutively active mutant Src in poorly metastatic K1735C23 cells increased invasion in vitro; whereas expression of a kinase-inactive Src mutant suppressed invasion. Our results suggest that signals initiated by vß3 promote metastasis in K1735 melanoma cells through the phosphorylation of FAK and activation of Src.

Key words: ß3 integrins, Melanoma, Focal adhesion kinase, Src, Motility

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