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 cytokine receptor superfamily, it activates the Janus kinase Jak2 which has tyrosine-kinase activity and initiates an activation of several key intracellular proteins (for example, mitogen-activated protein (MAP) kinases) that eventually execute the biological actions induced by growth hormone, including the expression of particular genes. In contrast to receptors that themselves have tyrosine kinase activity, the signalling pathways leading to MAP kinase activation that are triggered by growth hormone are poorly understood, but appear to be mediated by the proteins Grb2 and Shc. We now show that growth hormone stimulates tyrosine phosphorylation of the receptor for epidermal growth 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 growth-hormone-induced activation of MAP kinase and expression of the transcription 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 phosphorylation sites and Grb2-binding sites stimulated by growth hormone via Jak2. Our results indicate that the role of EGFR in signalling by growth hormone is to be phosphorylated by Jak2, thereby providing docking 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.
Yamauchi
T
T
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Ueki
K
K
Tobe
K
K
Tamemoto
H
H
Sekine
N
N
Wada
M
M
Honjo
M
M
Takahashi
M
M
Takahashi
T
T
Hirai
H
H
Tushima
T
T
Akanuma
Y
Y
Fujita
T
T
Komuro
I
I
Yazaki
Y
Y
Kadowaki
T
T
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016466:CHO Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D005786:Gene Expression Regulation; D016762:Genes, fos; D013006:Growth Hormone / Q000378:metabolism*; D006801:Humans; D053614:Janus Kinase 2; D008099:Liver / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D013006:Growth Hormone; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases