GROWTH HORMONE-INDUCED TYROSINE PHOSPHORYLATION OF EGF RECEPTOR AS ANESSENTIAL ELEMENT LEADING TO MAP KINASE ACTIVATION AND GENE-EXPRESSION

GH binding to its receptor, which belongs to the cytokine receptor sup erfamily, activates Janus kinase (JAK) 2 tyrosine kinase, thereby acti vating a number of intracellular key proteins such as STAT (signal tra nsducers and activators of transcription) proteins and mitogen-activat ed protein (MAP) kinases, which finally lead to GH's biological action s including gene expression. In contrast to receptor tyrosine kinases, the signalling pathways leading to MAP kinase activation by GH are po orly understood but appear to involve Grb2 and She. We now show that G H stimulated tyrosine phosphorylation of epidermal growth factor recep tor (EC;FR) and its association with Grb2, and concomitantly stimulate d MAP kinase activity in liver, a major target tissue. Expression of E GFR and its mutants into CHO-GH receptor (GHR) cells revealed that GH- induced full activation of MAP kinase and c-Jos expression required ty rosine phosphorylation sites of EGFR but not its intrinsic tyrosine ki nase activity. Moreover, by also using dominant negative JAK2 and in v itro kinase assay, we demonstrated that tyrosine 1068 of EGFR was evid ently one of the major phosphorylation and Grb2 binding sites stimulat ed by GH via JAK2. These data suggest that the role of EGFR in GH sign alling is to be phosphorylated by JAK2, thereby providing docking site s for Grb2 and activating MAP kinases and gene expression. This novel cross talk pathway may provide the first example of the hormone and cy tokine receptor superfamily transducing signals via associated nonrece ptor tyrosine kinase by phosphorylating growth factor receptor and uti lizing it as a docking protein independent of its receptor tyrosine ki nase activity.