Tyrosine phosphorylation of the EGF receptor by the kinase Jak2 is induced by growth hormone

Toshimasa Yamauchi, Kohjiro Ueki, Kazuyuki Tobe, Hiroyuki Tamemoto, Nobuo Sekine, Mitsufumi Wada, Masaru Honjo, Michio Takahashi, Tokiharu Takahashi, Hisamaru Hirai, Toshio Tushima, Yasuo Akanuma, Toshiro Fujita, Issei Komuro, Yoshio Yazaki and Takashi Kadowaki ()
Additional contact information
Toshimasa Yamauchi: Faculty of Medicine, University of Tokyo
Kohjiro Ueki: Faculty of Medicine, University of Tokyo
Kazuyuki Tobe: Faculty of Medicine, University of Tokyo
Hiroyuki Tamemoto: Faculty of Medicine, University of Tokyo
Nobuo Sekine: Faculty of Medicine, University of Tokyo
Mitsufumi Wada: Life Science Laboratories, Mitsui Toatsu Chemicals Inc.
Masaru Honjo: Life Science Laboratories, Mitsui Toatsu Chemicals Inc.
Michio Takahashi: Veterinary Medical Science, University of Tokyo
Tokiharu Takahashi: Faculty of Medicine, University of Tokyo
Hisamaru Hirai: Faculty of Medicine, University of Tokyo
Toshio Tushima: Tokyo Women's Medical College
Yasuo Akanuma: Institute for Diabetes Care and Research, Asahi Life Foundation
Toshiro Fujita: Faculty of Medicine, University of Tokyo
Issei Komuro: Faculty of Medicine, University of Tokyo
Yoshio Yazaki: Faculty of Medicine, University of Tokyo
Takashi Kadowaki: Faculty of Medicine, University of Tokyo

Nature, 1997, vol. 390, issue 6655, 91-96

Abstract: Abstract When growth hormone binds to its receptor, which belongs to the cytokine receptor superfamily1, it activates the Janus kinase Jak22 which has tyrosine-kinase activity and initiates an activation of several key intracellular proteins (for example, mitogen-activated protein (MAP) kinases3,4,5,6) 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 activation7,8 that are triggered by growth hormone are poorly understood, but appear to be mediated by the proteins Grb2 and Shc9. 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.

Date: 1997
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DOI: 10.1038/36369

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