Protein kinase-c activation inhibits tyrosine phosphorylation of the c-met protein.
The mature product of the c-met proto-oncogene is a putative tyrosine kinase receptor of 190 kd with an alpha beta heterodimeric structure. The c-met protein is phosphorylated in vivo on the beta subunit in the gastric carcinoma cell line GTL-16 (Giordano et al., 1988). Western blots with phosphotyrosine antibodies show that tyrosine phosphorylation of the beta subunit is reduced by treatment of GTL-16 cells with protein kinase C activators (tumor promoting phorbol esters such as phorbol 12-myristate 13-acetate, TPA, and beta-phorbol 12,13-dibutyrate, PdBu, or membrane permeable synthetic diacylglycerol 1-oleyl-2-acetyl-sn-glycerol, OAG). The inactive analog alpha-phorbol 12,13-didecanoate has no effect. The inhibition induced by TPA is dose dependent and maximal after 1 h. Depletion of protein kinase-C by prolonged treatment with TPA (18-48 h) increases the phosphorylation on tyrosine of the beta subunit. Phospho-amino acid analysis of the c-met protein immunoprecipitated from [32P]orthophosphate-labelled GTL-16 cells shows that protein kinase-C activation leads to an increase in serine phosphorylation and to concomitant decrease in tyrosine phosphorylation. These results suggest that, similar to the EGF and insulin receptor, the putative receptor encoded by the c-met proto-oncogene may be negatively modulated by protein kinase-C phosphorylation.
Gandino
L
L
Department of Biomedical Sciences and Oncology, University of Torino, Italy.
Di Renzo
M F
MF
Giordano
S
S
Bussolino
F
F
Comoglio
P M
PM
D000818:Animals; D004075:Diglycerides / Q000502:physiology; D005784:Gene Amplification; D015870:Gene Expression; D006801:Humans; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation; D011233:Precipitin Tests; D011493:Protein Kinase C / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met; D012694:Serine / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism*
D004075:Diglycerides; C000715470:MAS1 protein, human; D010703:Phorbol Esters; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D012694:Serine; D019859:Proto-Oncogene Proteins c-met; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate