title: Synergistic inhibition of cell migration by tetraspanin CD82 and gangliosides occurs via the EGFR or cMet-activated Pl3K/Akt signalling pathway.
abstract: The metastasis suppressor CD82/KAI-1, which is a member of the tetraspanin superfamily, has been proposed to exert its activity together with glycosphingolipids. However, the mechanism of CD82 inhibition has not been fully elucidated. The present study aimed to investigate the synergistic inhibition of cell migration by the tetraspanin CD82 and gangliosides and to correlate this inhibition with activation of epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (HGFR/cMet) in Hepa1-6 cell lines, whose motility and migration is stimulated by epidermal growth factor (EGF) and hepatocyte growth factor (HGF) in vitro. We found that Hepa1-6 cells transfected with the CD82 gene exhibited decreased migration in response to EGF and HGF. EGF-stimulated phosphorylation of EGFR at Tyr1173 was inhibited in these cells, which contributed to the attenuation of EGFR. Ectopic expression of CD82 in Hepa1-6 cells inhibited HGF-stimulated tyrosine phosphorylation of cMet at Tyr1313 and Tyr1365 without affecting the expression of cMet. These inhibitory effects were enhanced when CD82 was introduced with Ganglioside GM3 alone or GM2/GM3. Reduction of CD82 expression by RNA interference together with depletion of glycosphingolipids with P4 significantly enhanced cell motility and increased the expression of EGFR and its phosphorylation at Tyr1173 in response to EGF. Increased cell motility and HGF-dependent activation of cMet at Tyr1313 and Tyr1365 resulted from decreased CD82 levels and increased GM3. Furthermore, CD82 expression selectively attenuated EGFR and cMet signalling via phosphatidylinositol 3-kinase/Akt but had no affect on the activity of the MAPK signalling pathway. These results suggest that the synergistic effects of CD82 and GM3 or GM2/GM3 on EGFR expression and phosphorylation and cMet activation are responsible for CD82 inhibition of EGF- and HGF-dependent cell motility and migration of Hepa1-6 cells.
authors: Department of Clinical Laboratory, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China.
authors: Ying
authors: Y
authors: Li
authors: Xiaohua
authors: X
authors: Huang
authors: Jianing
authors: J
authors: Zhang
authors: Yuzhong
authors: Y
authors: Li
authors: Keli
authors: K
authors: Ma
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005678:G(M2) Ganglioside / Q000494:pharmacology; D005679:G(M3) Ganglioside / Q000494:pharmacology; D005732:Gangliosides / Q000494:pharmacology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D051861:Kangai-1 Protein / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C497689:Cd82 antigen, mouse; D005679:G(M3) Ganglioside; D005732:Gangliosides; D051861:Kangai-1 Protein; D005678:G(M2) Ganglioside; D019000:Phosphotyrosine; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; CD82/KAI-1; EGFR; GM3; HGFR; Metastasis