Association of tetraspanin CD9 with transmembrane TGF{alpha} confers alterations in cell-surface presentation of TGF{alpha} and cytoskeletal organization.
Ligand presentation is a major determinant of receptor activation. The epidermal growth factor receptor (EGFR), a tyrosine kinase receptor, is activated by growth factors of the transforming growth factor alpha (TGFalpha) family. The tetraspanin CD9 interacts with transmembrane TGFalpha and decreases its ectodomain shedding to release soluble TGFalpha. Here we report that CD9 has a role in the maturation of transmembrane TGFalpha and its stabilization at the cell surface, and in the cell-surface distribution in polarized epithelial cells. Furthermore, coexpression of CD9 and TGFalpha confers changes in cytoskeletal organization with a decrease in actin stress fibers and focal adhesions, and changes in RhoA and Rac1 GTPase activity. These alterations are reversed by blocking EGFR signaling. Finally, we demonstrate changes in cell adhesion and migration resulting from coexpression of TGFalpha with CD9. These results provide insight into the role of CD9 in the presentation of TGFalpha in epithelial and carcinoma cells, whose physiology is driven by ligand-induced EGFR activation.
Department of Cell and Tissue Biology, Program in Cell Biology, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
Isabella
I
Imhof
Warren J
WJ
Gasper
Rik
R
Derynck
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D016764:Cell Polarity; D006224:Cricetinae; D003599:Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D004285:Dogs; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction; D060245:Tetraspanin 29; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000378:metabolism*
D015703:Antigens, CD; C554869:CD9 protein, human; C554870:Cd9 protein, mouse; D008562:Membrane Glycoproteins; D060245:Tetraspanin 29; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors