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© The Rockefeller University Press, 0021-9525/2000//591 $5.00
The Journal of Cell Biology, Volume 148, Number 3, , 2000 591-602

Original Article

The Tetraspanin Cd9 Associates with Transmembrane TGF-{alpha} and Regulates TGF-{alpha}–Induced Egf Receptor Activation and Cell Proliferation



Wen Shia,b, Huizhou Fana,b, Lillian Shuma,b, and Rik Deryncka,b

a Department of Growth and Development, Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, California 94143
b Department of Anatomy, Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, California 94143
Department of Growth and Development, University of California at San Francisco, San Francisco, CA 94143-0640.(415) 476-1499(415) 476-7322

derynck{at}itsa.ucsf.edu

Transforming growth factor-{alpha} (TGF-{alpha}) is a member of the EGF growth factor family. Both transmembrane TGF-{alpha} and the proteolytically released soluble TGF-{alpha} can bind to the EGF/TGF-{alpha} tyrosine kinase receptor (EGFR) and activate the EGFR-induced signaling pathways. We now demonstrate that transmembrane TGF-{alpha} physically interacts with CD9, a protein with four membrane spanning domains that is frequently coexpressed with TGF-{alpha} in carcinomas. This interaction was mediated through the extracellular domain of transmembrane TGF-{alpha}. CD9 expression strongly decreased the growth factor– and PMA- induced proteolytic conversions of transmembrane to soluble TGF-{alpha} and strongly enhanced the TGF- {alpha}–induced EGFR activation, presumably in conjunction with increased expression of transmembrane TGF-{alpha}. In juxtacrine assays, the CD9-induced EGFR hyperactivation by transmembrane TGF-{alpha} resulted in increased proliferation. In contrast, CD9 coexpression with transmembrane TGF-{alpha} decreased the autocrine growth stimulatory effect of TGF-{alpha} in epithelial cells. This decrease was associated with increased expression of the cdk inhibitor, p21CIP1. These data reveal that the association of CD9 with transmembrane TGF-{alpha} regulates ligand-induced activation of the EGFR, and results in altered cell proliferation.

Key Words: transforming growth factor-{alpha} • CD9 • epidermal growth factor receptor • ectodomain • shedding

© 2000 The Rockefeller University Press

The present address for L. Shum is Craniofacial Development Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-2745.

Abbreviations used in this paper: EGFR, EGF/TGF-{alpha} tyrosine kinase receptor; HB-EGF, heparin-binding EGF-like growth factor; MAP, mitogen-activated protein; TGF-{alpha}, transforming growth factor-{alpha}.


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