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A new protein containing an SH2 domain that inhibits JAK kinases

Nature volume 387, pages 921–924 (1997)Cite this article

Abstract

The proliferation and differentiation of cells of many lineages are regulated by secreted proteins known as cytokines. Cytokines exert their biological effect through binding to cell-surface receptors that are associated with one or more members of the JAK family of cytoplasmic tyrosine kinases. Cytokine-induced receptor dimerization leads to the activation of JAKs, rapid tyrosine-phosphorylation of the cytoplasmic domains, and subsequent recruitment of various signalling proteins, including members of the STAT family of transcription factors, to the receptor complex1,2,3,4,5. Using the yeast two-hybrid system, we have now isolated a new SH2-domain-containing protein, JAB, which is a JAK-binding protein that interacts with the Jak2 tyrosine-kinase JH1 domain6. JAB is structurally related to CIS, a cytokine-inducible SH2 protein7,8. Interaction of JAB with Jak1, Jak2 or Jak3 markedly reduces their tyrosine-kinase activity and suppresses the tyrosine-phosphorylation and activation of STATs. JAB and CIS appear to function as negative regulators in the JAK signalling pathway.

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Figure 1: Two-hybrid analysis of Jak2 JH1 and JAB stained by in situ β-galactosidase assay (a–c) and sequence comparison between murine JAB and CIS (d).
Figure 2: Interaction between Jak2 and JAB in vitro.
Figure 3: Association of Jak2 with JAB and inhibition of JAK kinase reaction in vivo.
Figure 4: Inhibition of JAK activity by JAB in cells assessed by reporter assay.

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Acknowledgements

We thank H. Ohgusu for technical assistance, T. Hirano for the APRE/jun promoter construct and STAT3 cDNA, R. Fukunaga for Jak2, A. F. Wilks for the Jak1, T. Shirasawa for rat Jak3 cDNAs, and D. Hilton and R. Starr for reading and editing the manuscript. Part of this work was supported by grants from the Ministry of Science, Education and Culture of Japan, the Kato Memorial Foundation, the Haraguchi Memorial Foundation, the Uehara Memorial Foundation, the Kowa Life Science Foundation, the Motida Memorial Science Foundation and the Naito Memorial Foundation.

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  1. Takaho A. Endo, Masaaki Masuhara, Masahiro Yokouchi and Yuzuru Kanakura: These authors contributed equally to this work.

Authors and Affiliations

  1. *Institute of Life Science, Kurume University, Aikawamachi 2432-3, 839, Kurume, Japan

    Takaho A. Endo, Masaaki Masuhara, Masahiro Yokouchi, Ritsu Suzuki, Hiroshi Sakamoto, Kaoru Mitsui, Akira Matsumoto, Shyu Tanimura, Motoaki Ohtsubo, Hiroyuki Misawa & Akihiko Yoshimura

  2. ‡Department of Orthopedic Surgery, Kurume University, Aikawamachi 2432-3, 839, Kurume, Japan

    Masahiro Yokouchi, Ritsu Suzuki & Seturo Komiya

  3. §Department of Immunology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, 113, Tokyo, Japan

    Tadaaki Miyazaki, Nogueira Leonor & Tadatsugu Taniguchi

  4. ‖Department of Tumor Cell Biology, The Tokyo Metropolitan Institute of Medical Science, Bunkyouku, 113, Tokyo, Japan

    Takashi Fujita

  5. ¶Department of Hematology and Oncology, Osaka University Medical School, 565, Suita, Japan

    Yuzuru Kanakura

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  1. Takaho A. Endo
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Correspondence to Akihiko Yoshimura.

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Endo, T., Masuhara, M., Yokouchi, M. et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387, 921–924 (1997). https://doi.org/10.1038/43213

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