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Letters to Nature

Nature 387, 921-924 (26 June 1997) | ; Received 17 March 1997; Accepted 2 May 1997

A new protein containing an SH2 domain that inhibits JAK kinases

Takaho A. Endo1,2, Masaaki Masuhara1,2, Masahiro Yokouchi1,2,3, Ritsu Suzuki1,3, Hiroshi Sakamoto1, Kaoru Mitsui1, Akira Matsumoto1, Shyu Tanimura1, Motoaki Ohtsubo1, Hiroyuki Misawa1, Tadaaki Miyazaki4, Nogueira Leonor4, Tadatsugu Taniguchi4, Takashi Fujita5, Yuzuru Kanakura6, Seturo Komiya3 & Akihiko Yoshimura1

  1. Institute of Life Science, Kurume University, Aikawamachi 2432-3 Kurume 839, Japan
  2. These authors contributed equally to this work.
  3. Department of Orthopedic Surgery, Kurume University, Aikawamachi 2432-3 Kurume 839, Japan
  4. Department of Immunology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113, Japan
  5. Department of Tumor Cell Biology, The Tokyo Metropolitan Institute of Medical Science, Bunkyouku, Tokyo 113, Japan
  6. Department of Hematology and Oncology, Osaka University Medical School, Suita 565, Japan

Correspondence to: Akihiko Yoshimura1 Correspondence and requests for materials should be addressed to A.Y. (Email: yosimura@lsi.kurume-u.ac.jp). The nucleotide sequence data reported here will appear in the DDBJ, EMBL and GenBank nucleotide sequence databases under accession numbers AB 000676 (human JAB) and AB 000677 (mouse JAB).

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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.