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

Nature volume 390, pages 91–96 (1997)Cite this article

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.

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Figure 1: GH-stimulated tyrosine phosphorylation of EGFR and its association with Grb2, and concomitantly stimulated MAP kinase activity in liver in vivo.
Figure 2: Tyrosine phosphorylation of EGFR enhances GH-induced MAP-kinase activation.
Figure 3: GH-induced full activation of MAP kinase and gene expression requires tyrosine-phosphorylation sites of EGFR but not EGFR intrinsic kinase activity.
Figure 4: Tyrosine 1068 of EGFR was one of the major phosphorylation and Grb2-binding sites stimulated by GH via Jak2.

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Acknowledgements

We thank I. Kerr and G. Stark for γ2A/GHR, C. Wollheim for INS-1, H. Green for 3T3 F442A cells, J. Ihle for Jak2 cDNA, K. Arai for expression vectors of Jak2 and dominant-negative Jak2 (ΔJak2), H. Sabe for Csk expression vector, I. Saitoh for Adex1CALacZ and the expression cosmid cassette, Y. Okabayashi and M. Kasuga and S. Kakinuma for technical assistance. This work was supported by grants from the research fellowships of the Japan Society for the Promotion of Science for Young Scientists (to T.Y.), from the Ministry of Education, Science, Sports, and Culture and the Ministry of Health and Welfare of Japan (to T.K.) and for diabetes research from the Taisho Pharmaceutical Co. Ltd. (to T.K.).

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Author notes

  1. Toshimasa Yamauchi, Kohjiro Ueki and Yasuo Akanuma: These authors contributed equally to this work.

Authors and Affiliations

  1. Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, 113, Japan

    Toshimasa Yamauchi, Kohjiro Ueki, Kazuyuki Tobe, Hiroyuki Tamemoto, Tokiharu Takahashi, Hisamaru Hirai, Issei Komuro, Yoshio Yazaki & Takashi Kadowaki

  2. Fourth Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, 112, Japan

    Nobuo Sekine & Toshiro Fujita

  3. Life Science Laboratories, Mitsui Toatsu Chemicals Inc., Mobara, 297, Japan

    Mitsufumi Wada & Masaru Honjo

  4. Department of Veterinary Physiology, Veterinary Medical Science, University of Tokyo, Tokyo, 113, Japan

    Michio Takahashi

  5. Second Department of Internal Medicine, Tokyo Women's Medical College, Tokyo, 162, Japan

    Toshio Tushima

  6. Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, 100, Japan

    Yasuo Akanuma

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  1. Toshimasa Yamauchi
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Correspondence to Takashi Kadowaki.

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Yamauchi, T., Ueki, K., Tobe, K. et al. Tyrosine phosphorylation of the EGF receptor by the kinase Jak2 is induced by growth hormone. Nature 390, 91–96 (1997). https://doi.org/10.1038/36369

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