TYROSINE PHOSPHORYLATION OF THE EGF RECEPTOR BY THE KINASE JAK2 IS INDUCED BY GROWTH-HORMONE

When growth hormone binds to its receptor, which belongs to the cytoki ne receptor superfamily(1), it activates the Janus kinase Jak2(2) whic h has tyrosine-kinase activity and initiates an activation of several key intracellular proteins (for example, mitogen-activated protein (MA P) kinases(3-6)) that eventually execute the biological actions induce d by growth hormone, including the expression of particular genes. In contrast to receptors that themselves have tyrosine kinase activity, t he signalling pathways leading to MAP kinase activation(7,8) that are triggered by growth hormone are poorly understood, but appear to be me diated by the proteins GrB2 and Shc(9). We now show that growth hormon e stimulates tyrosine phosphorylation of the receptor for epidermal gr owth factor (EGFR) and its association with Grb2 and at the same time stimulates MAP kinase activity in liver, an important target tissue of growth hormone, Expression of EGFR and its mutants revealed that grow th-hormone-induced activation of MAP kinase and expression of the tran scription factor c-fos requires phosphorylation of tyrosines on EGFR, but not its own intrinsic tyrosine-kinase activity, Moreover, tyrosine at residue 1,068 of the EGFR is proposed to be one of the principal p hosphorylation sires and Grb2-binding sites stimulated by growth hormo ne via Jak2. Our results indicate that the role of EGFR in signalling by growth hormone is to be phosphorylated by Jak2, thereby providing d ocking sites for Grb2 and activating MAP kinases and gene expression, independently of the intrinsic tyrosine kinase activity of EGFR. This may represent a novel cross-talk pathway between the cytokine receptor superfamily and growth factor receptor.