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Hes binding to STAT3 mediates crosstalk between Notch and JAK–STAT signalling

Nature Cell Biology volume 6, pages 547–554 (2004)Cite this article

Abstract

Although the Notch and JAK–STAT signalling pathways fulfill overlapping roles in growth and differentiation regulation, no coordination mechanism has been proposed to explain their relationship. Here we show that STAT3 is activated in the presence of active Notch, as well as the Notch effectors Hes1 and Hes5. Hes proteins associate with JAK2 and STAT3, and facilitate complex formation between JAK2 and STAT3, thus promoting STAT3 phosphorylation and activation. Furthermore, suppression of endogenous Hes1 expression reduces growth factor induction of STAT3 phosphorylation. STAT3 seems to be essential for maintenance of radial glial cells and differentiation of astrocytes by Notch in the developing central nervous system. These results suggest that direct protein–protein interactions coordinate cross-talk between the Notch–Hes and JAK–STAT pathways.

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Figure 1: Activation of STAT3 by Notch and its downstream effectors Hes1 and Hes5.
Figure 2: Induction of STAT3 phosphorylation by Notch and Hes proteins.
Figure 4: Hes1 coprecipitates with JAK2.
Figure 3: Direct interaction of Hes proteins with STAT3.
Figure 5: STAT3 is essential for promotion of radial glia and astrocytic differentiation by Notch.

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Acknowledgements

We thank T. Hirano, M. Hibi, T. Taga, K. Nakashima, R. Kageyama, T. Kitamura, T. Iso, T. Sudo, A. Miyajima, T. Kinoshita and R. S. Datta for reagents and advice. We also thank K. Nakajima and H. Tabata for technical help. We are grateful to R. Dolmetsch, M.E. Greenberg, T. Curran, K. Matsumoto and A. Yoshimura for critical reading of the manuscript. We also thank other members of the Gotoh laboratory for their encouragement and helpful discussions. This work is supported by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan, by PRESTO21 and CREST of the Japan Science and Technology Corporation and VRIA research foundation.

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Authors and Affiliations

  1. Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan

    Sachiko Kamakura, Koji Oishi, Takeshi Yoshimatsu, Norihisa Masuyama & Yukiko Gotoh

  2. Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, 45229, OH, USA

    Masato Nakafuku

  3. PRESTO and CREST Research Projects, Japan Science and Technology Corporation, Tokyo, Japan

    Yukiko Gotoh

  4. National Institute for Physiological Sciences, 444-8585, Myodaiji, Okazaki, Japan

    Yukiko Gotoh

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  1. Sachiko Kamakura
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Correspondence to Yukiko Gotoh.

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Kamakura, S., Oishi, K., Yoshimatsu, T. et al. Hes binding to STAT3 mediates crosstalk between Notch and JAK–STAT signalling. Nat Cell Biol 6, 547–554 (2004). https://doi.org/10.1038/ncb1138

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