Tetraspanin CD81 is linked to ERK/MAPKinase signaling by Shc in liver tumor cells.
Tetraspanins is a large family of membrane proteins that are implicated in cell proliferation, differentiation and tumor invasion. Specifically, the tetraspanin CD81 has been involved in cell proliferation but the mechanism is unknown. Here, we show that CD81 clustering stimulates ERK/MAPKinase activity and tyrosine phosphorylation of the adapter protein Shc in Huh7 cancer cells. In addition, overexpression of CD81 in HepG2 cells, NIH3T3 cells, and murine fibroblasts GD25 lacking the beta1 family of integrins induces cell proliferation and ERK/MAPKinase activation. Linked with this event, we observed an increase in CD81-associated type II phosphatidylinositol 4-kinase activity. A mutant in the PTB domain of Shc failed to interact with phosphoinositides and localize to the plasma membrane thus blocking CD81-induced ERK/MAPKinase activation. Therefore, we conclude that CD81 stimulates synthesis of phosphoinositides with the recruitment of Shc to the plasma membrane via PTB domain, and this sequence of events induces activation of ERK/MAPKinase. These findings define a novel mechanism of ERK/MAPKinase activation and tumor cell proliferation.
Carloni
Vinicio
V
Dipartimento di Medicina Interna, Università di Firenze, Viale Morgagni, 85, I-50134 Firenze, Italy. v.carloni@dfc.unifi.it
Mazzocca
Antonio
A
Ravichandran
Kodimangalam S
KS
D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D041681:NIH 3T3 Cells; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D060225:Tetraspanin 28
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD; C554798:CD81 protein, human; C554799:Cd81 protein, mouse; D008565:Membrane Proteins; D018129:Phosphatidylinositol Phosphates; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D060225:Tetraspanin 28; C037178:phosphatidylinositol 4-phosphate; D019870:1-Phosphatidylinositol 4-Kinase; D020928:Mitogen-Activated Protein Kinases