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

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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Correspondence to Yukiko Gotoh.

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Fig. S1, Fig. S2, Fig. S3 and Fig. S4 (PDF 1534 kb)

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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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