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First published online 4 August 2009
doi: 10.1242/jcs.045658

Journal of Cell Science 122, 3137-3144 (2009)
Published by The Company of Biologists 2009
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Research Article

Engagement of CD81 induces ezrin tyrosine phosphorylation and its cellular redistribution with filamentous actin

Greg P. Coffey1, Ranjani Rajapaksa1, Raymond Liu1, Orr Sharpe2, Chiung-Chi Kuo1, Sharon Wald Krauss3, Yael Sagi1, R. Eric Davis4, Louis M. Staudt4, Jeff P. Sharman1, William H. Robinson2 and Shoshana Levy1,*

1 Stanford University, School of Medicine, Division of Oncology, Stanford, CA 94305, USA
2 Stanford University, School of Medicine, Division of Immunology and Rheumatology, GRECC Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA
3 Life Sciences Division, University of California Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
4 Metabolism Branch, National Cancer Institute, Bethesda, MD 20892, USA

* Author for correspondence (slevy{at}stanford.edu)

Accepted 10 June 2009

CD81 is a tetraspanin family member involved in diverse cellular interactions in the immune and nervous systems and in cell fusion events. However, the mechanism of action of CD81 and of other tetraspanins has not been defined. We reasoned that identifying signaling molecules downstream of CD81 would provide mechanistic clues. We engaged CD81 on the surface of B-lymphocytes and identified the induced tyrosine-phosphorylated proteins by mass spectrometry. This analysis showed that the most prominent tyrosine phosphorylated protein was ezrin, an actin-binding protein and a member of the ezrin-radixin-moesin family. We also found that CD81 engagement induces spleen tyrosine kinase (Syk) and that Syk was involved in tyrosine phosphorylation of ezrin. After engagement of CD81, it colocalized with ezrin and F-actin, and this association was disrupted when Syk activation was blocked. Taken together, these studies suggest a model in which CD81 interfaces between the plasma membrane and the cytoskeleton by activating Syk, mobilizing ezrin, and recruiting F-actin to facilitate cytoskeletal reorganization and cell signaling. This mechanism might explain the pleiotropic effects induced in response to stimulation of cells by anti-CD81 antibodies or by the hepatitis C virus, which uses this molecule as its key receptor.

Key words: Tetraspanins, Signal transduction, Syk


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© The Company of Biologists Ltd 2009