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J. Biol. Chem., Vol. 281, Issue 18, 12976-12985, May 5, 2006

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Contrasting Effects of EWI Proteins, Integrins, and Protein Palmitoylation on Cell Surface CD9 Organization^*

Xiuwei H. Yang, Oleg V. Kovalenko, Tatiana V. Kolesnikova, Milena M. Andzelm, Eric Rubinstein^¶, Jack L. Strominger, and Martin E. Hemler¹

From the Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, the Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, and ^¶Inserm U268, Institut Andre Lwoff, Universite Paris XI, 94807 Villejuif, Cedex, France

CD9, a tetraspanin protein, makes crucial contributions to sperm egg fusion, other cellular fusions, epidermal growth factor receptor signaling, cell motility, and tumor suppression. Here we characterize a low affinity anti-CD9 antibody, C9BB, which binds preferentially to homoclustered CD9. Using mAb C9BB as a tool, we show that cell surface CD9 homoclustering is promoted by expression of 31 and 64 integrins and by palmitoylation of the CD9 and 4 proteins. Conversely, CD9 is shifted toward heteroclusters upon expression of CD9 partner proteins (EWI-2 and EWI-F) or other tetraspanins, or upon ablation of CD9 palmitoylation. Furthermore, unpalmitoylated CD9 showed enhanced EWI-2 association, thereby demonstrating a previously unappreciated role for tetraspanin palmitoylation, and underscoring how depalmitoylation and EWI-2 association may collaborate to shift CD9 from homo- to heteroclusters. In conclusion, we have used a novel molecular probe (mAb C9BB) to demonstrate the existence of multiple types of CD9 complex on the cell surface. A shift from homo- to heteroclustered CD9 may be functionally significant because the latter was especially obvious on malignant epithelial tumor cells. Hence, because of its specialized properties, C9BB may be more useful than other anti-CD9 antibodies for monitoring CD9 during tumor progression.

Received for publication, September 28, 2005 , and in revised form, March 10, 2006.

^* This work was supported by awards from the DFCI Friends Foundation and a DFCI Claudia Adams Barr grant (to X. H. Y.) and National Institutes of Health Grants GM38903 and CA42368 (to M. E. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental figures and tables.

¹ To whom correspondence should be addressed: Dana-Farber Cancer Inst., Rm D-1430, 44 Binney St., Boston, MA 02115. Tel.: 617-632-3410; Fax: 617-632-2662; E-mail: Martin_Hemler{at}DFCI.Harvard.edu.

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