Growth hormone-induced tyrosine phosphorylation of EGF receptor as an essential element leading to MAP kinase activation and gene expression.
GH binding to its receptor, which belongs to the cytokine receptor superfamily, activates Janus kinase (JAK) 2 tyrosine kinase, thereby activating a number of intracellular key proteins such as STAT (signal transducers and activators of transcription) proteins and mitogen-activated protein (MAP) kinases, which finally lead to GH's biological actions including gene expression. In contrast to receptor tyrosine kinases, the signalling pathways leading to MAP kinase activation by GH are poorly understood but appear to involve Grb2 and Shc. We now show that GH stimulated tyrosine phosphorylation of epidermal growth factor receptor (EGFR) and its association with Grb2, and concomitantly stimulated MAP kinase activity in liver, a major target tissue. Expression of EGFR and its mutants into CHO-GH receptor (GHR) cells revealed that GH-induced full activation of MAP kinase and c-fos expression required tyrosine phosphorylation sites of EGFR but not its intrinsic tyrosine kinase activity. Moreover, by also using dominant negative JAK2 and in vitro kinase assay, we demonstrated that tyrosine 1068 of EGFR was evidently one of the major phosphorylation and Grb2 binding sites stimulated by GH via JAK2. These data suggest that the role of EGFR in GH signalling is to be phosphorylated by JAK2, thereby providing docking sites for Grb2 and activating MAP kinases and gene expression. This novel cross talk pathway may provide the first example of the hormone and cytokine receptor superfamily transducing signals via associated nonreceptor tyrosine kinase by phosphorylating growth factor receptor and utilizing it as a docking protein independent of its receptor tyrosine kinase activity.
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
Tsushima
T
T
Akanuma
Y
Y
Fujita
T
T
Komuro
I
I
Yazaki
Y
Y
Kadowaki
T
T
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D015971:Gene Expression Regulation, Enzymologic; D013006:Growth Hormone / Q000502:physiology*; D006801:Humans; D053614:Janus Kinase 2; D008099:Liver / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D014443:Tyrosine / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D013006:Growth Hormone; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases