Regulation of c-Met signaling by the tetraspanin KAI-1/CD82 affects cancer cell migration.
It has been proposed that the metastasis suppressor CD82/KAI-1, which is a member of the tetraspanin superfamily, regulates biological activity by associating with cell surface receptors or proteins. We show a novel association between CD82 and the hepatocyte growth factor (HGF) receptor c-Met. Although ectopic expression of CD82 in nonsmall cell lung carcinoma cells did not affect the tyrosine phosphorylation of c-Met, these cells showed significant suppression of HGF-induced lamellipodial protrusion and cell migration. CD82 selectively attenuated c-Met signaling via the Ras-Cdc42/Rac and the phosphatidylinositol 3-kinase/Cdc42/Rac pathways. In contrast, another c-Met signaling pathway that involves phosphatidylinositol 3-kinase/Akt and phosphatidylinositol 3-kinase/mitogen activated protein kinase was not affected by CD82. Signaling adapter proteins for c-Met, such as Grb2 and p85, exhibited reduced association with c-Met in cells that ectopically expressed CD82. These results indicate that the CD82-c-Met complex inhibits HGF-induced cancer cell migration by the inactivation of small GTP-binding proteins of the Rho family via c-Met adapter proteins.
Takahashi
Miho
M
Department of Oral and Maxillofacial Surgery, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan.
Sugiura
Tsuyoshi
T
Department of Oral and Maxillofacial Surgery, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan.
Abe
Masakazu
M
Department of Oral and Maxillofacial Surgery, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan.
Ishii
Koutaro
K
Department of Oral and Maxillofacial Surgery, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan.
Shirasuna
Kanemitsu
K
Department of Oral and Maxillofacial Surgery, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan.
D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000906:Antibodies / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D051861:Kangai-1 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D051861:Kangai-1 Protein; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D018631:ras Proteins; D020741:rho GTP-Binding Proteins