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| The EMBO Journal
(1999) 18, 1309–1320, doi:10.1093/emboj/18.5.1309 |
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| The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop |
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| Hideo Yasukawa1, 2, Hiroyuki Misawa1, 3, Hiroshi Sakamoto1, Masaaki Masuhara1, Atsuo Sasaki1, Toru Wakioka1, 4, Satoshi Ohtsuka1, Tsutomu Imaizumi2, Tadashi Matsuda5, 6, James N. Ihle5 and Akihiko Yoshimura1 |
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1 Institute of Life Science, Kurume University, Aikawa-machi 2432-3 Kurume 839-0861, Japan 2 Department of Internal Medicine (III), Kurume University, Asahi-machi, Kurume 830-0011, Japan 3 Present address: Laboratory of Endocrinology and Molecular Metabolism, Graduate School of Nutritional Sciences, University of Shizuoka, Shizuoka 422-8526, Japan 4 Department of Orthopedic Surgery, Faculty of Medicine, Kurume University, Asahi-machi, Kurume 830-0011, Japan 5 Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN, USA 6 Present address: Department of Immunology, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan To whom correspondence should be addressed Akihiko Yoshimura, yosimura@lsi.kurume-u.ac.jp Received 29 September 1998; Revised 23 December 1998; Accepted 31 December 1998. |
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| Abstract |
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| The Janus family of protein tyrosine kinases (JAKs) regulate cellular processes involved in cell growth, differentiation and transformation through their association with cytokine receptors. However, compared with other kinases, little is known about cellular regulators of the JAKs. We have recently identified a JAK-binding protein (JAB) that inhibits JAK signaling in cells. In the studies presented here we demonstrate that JAB specifically binds to the tyrosine residue (Y1007) in the activation loop of JAK2, whose phosphorylation is required for activation of kinase activity. Binding to the phosphorylated activation loop requires the JAB SH2 domain and an additional N-terminal 12 amino acids (extended SH2 subdomain) containing two residues (Ile68 and Leu75) that are conserved in JAB-related proteins. An additional N-terminal 12-amino-acid region (kinase inhibitory region) of JAB also contributes to high-affinity binding to the JAK2 tyrosine kinase domain and is required for inhibition of JAK2 signaling and kinase activity. Our studies define a novel type of regulation of tyrosine kinases and might provide a basis for the design of specific tyrosine kinase inhibitors. |
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| Keywords: activation loop, CIS, JAB, JAK, SH2 domain |
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