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J. Biol. Chem., Vol. 278, Issue 29, 26323-26326, July 18, 2003

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The Tetraspanin CD151 Functions as a Negative Regulator in the Adhesion-dependent Activation of Ras^*

Shigeaki Sawada , Mitsunori Yoshimoto , Elena Odintsova , Neil A. Hotchin  and Fedor Berditchevski  ¶

From the Cancer Research UK Institute for Cancer Studies and School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TA, United Kingdom

Transmembrane proteins of the tetraspanin superfamily are associated with integrins and are thought to regulate adhesion-dependent signaling. The molecular mechanisms of this regulation remain unknown. We used rat fibroblasts to analyze the contribution of the tetraspanin CD151 in the adhesion-dependent signaling. Expression of CD151 specifically attenuated adhesion-dependent activation of Ras. Furthermore, activation of PKB/c-Akt and ERK1/2, downstream targets in the Ras signaling pathway, was also diminished in cells expressing CD151. In contrast, adhesion-dependent activation of FAK and c-Src were not affected by CD151. The attenuation of Ras signaling did not correlate with phosphorylation of Tyr⁹²⁵-FAK, tyrosine phosphorylation of Shc, or with assembly of the p120RasGAP-p62Dok complex. Using mutants of CD151 we established that the cytoplasmic C-terminal portion is critical for activity of CD151 toward Ras. Taken together these results identify CD151 as a negative regulator of Ras and suggest a novel mechanism of adhesion-dependent regulation of Ras activity.

Received for publication, May 16, 2003 , and in revised form, May 29, 2003.

^* This work was supported by Cancer Research UK (SP2369/0201 (to F. B.)) and by the Biotechnology and Biological Sciences Research Council (6/C17261 (to N. A. H. and F. 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: Cancer Research UK Inst. for Cancer Studies, The University of Birmingham, Egdbaston, Birmingham B15 2TA, UK. Tel.: 44-121-414-2801; Fax: 44-121-414-4486; E-mail: f.berditchevski{at}bham.ac.uk.

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