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 phosph orylation of the downstream adaptor protein Gab1 is required for the HGF re sponse, Here we show that serine/threonine phosphorylation of Gab1 provides a control mechanism for negative regulation. Treatment,vith okadaic acid, a potent inhibitor of the serine/threonine protein phosphatases PP1 and PP2 A, was followed by activation of a number of serine/threonine kinases, hype r-phosphorylation in serine and threonine of Gab1 and se, ere inhibition of the HGF-induced biological responses, Under these conditions, Gab1 nas fou nd to be concomitantly hypophosphorylated in tyrosine, and thus endowed wit h reduced ability to recruit SH2 containing signal transducers such as PI3 kinase. Among the serine-threonine kinases activated bg PP1 and PP2A inhibi tion, we found that PKC-alpha and PKC-beta1 are required for negative regul ation of Gab1, These data pro,ide a novel negative mechanism for the HGF re ceptor signaling pathways and highlight a potentially useful target for inh ibitors of invasive growth.