The tetraspanin CD9 associates with transmembrane TGF-alpha and regulates TGF-alpha-induced EGF receptor activation and cell proliferation.
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, p21(CIP1). 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.
Shi
W
W
Department of Growth and Development, Program in Cell Biology, University of California at San Francisco, San Francisco, California 94143, USA.
Fan
H
H
Shum
L
L
Derynck
R
R
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D015870:Gene Expression; D008562:Membrane Glycoproteins; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D060245:Tetraspanin 29; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008562:Membrane Glycoproteins; D060245:Tetraspanin 29; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors; D013755:Tetradecanoylphorbol Acetate