Original Article

The Tetraspanin CD9 Associates with Transmembrane TGF- and Regulates TGF-–induced EGF Receptor Activation and Cell Proliferation

Correspondence to: Rik Derynck, Department of Growth and Development, University of California at San Francisco, San Francisco, CA 94143-0640. Tel:(415) 476-7322 Fax:(415) 476-1499 E-mail:derynck{at}itsa.ucsf.edu.

Transforming growth factor- (TGF-) is a member of the EGF growth factor family. Both transmembrane TGF- and the proteolytically released soluble TGF- can bind to the EGF/TGF- tyrosine kinase receptor (EGFR) and activate the EGFR-induced signaling pathways. We now demonstrate that transmembrane TGF- physically interacts with CD9, a protein with four membrane spanning domains that is frequently coexpressed with TGF- in carcinomas. This interaction was mediated through the extracellular domain of transmembrane TGF-. CD9 expression strongly decreased the growth factor– and PMA- induced proteolytic conversions of transmembrane to soluble TGF- and strongly enhanced the TGF- –induced EGFR activation, presumably in conjunction with increased expression of transmembrane TGF-. In juxtacrine assays, the CD9-induced EGFR hyperactivation by transmembrane TGF- resulted in increased proliferation. In contrast, CD9 coexpression with transmembrane TGF- decreased the autocrine growth stimulatory effect of TGF- in epithelial cells. This decrease was associated with increased expression of the cdk inhibitor, p21^CIP1. These data reveal that the association of CD9 with transmembrane TGF- regulates ligand-induced activation of the EGFR, and results in altered cell proliferation.

Key Words: transforming growth factor-, CD9, epidermal growth factor receptor, ectodomain, shedding

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