Gab1 phosphorylation: a novel mechanism for negative regulation of HGF receptor signaling.
Signal transduction by HGF receptor, the tyrosine kinase encoded by the MET oncogene, switches on a genetic program called 'invasive growth' inducing epithelial cell dissociation, migration, growth, and ultimately leading to differentiation into branched tubular structures. Sustained tyrosine phosphorylation of the downstream adaptor protein Gab1 is required for the HGF response. Here we show that serine/threonine phosphorylation of Gab1 provides a control mechanism for negative regulation. Treatment with okadaic acid, a potent inhibitor of the serine/threonine protein phosphatases PP1 and PP2A, was followed by activation of a number of serine/threonine kinases, hyper-phosphorylation in serine and threonine of Gab1 and severe inhibition of the HGF-induced biological responses. Under these conditions, Gab1 was found to be concomitantly hypo-phosphorylated in tyrosine, and thus endowed with reduced ability to recruit SH2 containing signal transducers such as PI3 kinase. Among the serine-threonine kinases activated by PP1 and PP2A inhibition, we found that PKC-alpha and PKC-beta1 are required for negative regulation of Gab1. These data provide a novel negative mechanism for the HGF receptor signaling pathways and highlight a potentially useful target for inhibitors of invasive growth.
Gual
P
P
Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Str. Prov. 142, Km 3.95, 10060 Candiolo, Italy.
Giordano
S
S
Anguissola
S
S
Parker
P J
PJ
Comoglio
P M
PM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002450:Cell Communication; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D013912:Threonine / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; C098587:GAB1 protein, human; D007527:Isoenzymes; D010750:Phosphoproteins; D019319:Okadaic Acid; D013912:Threonine; D012694:Serine; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; C496628:PRKCA protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D010749:Phosphoprotein Phosphatases; D019311:Staurosporine