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The JAK‐binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop
Author(s) -
Yasukawa Hideo,
Misawa Hiroyuki,
Sakamoto Hiroshi,
Masuhara Masaaki,
Sasaki Atsuo,
Wakioka Toru,
Ohtsuka Satoshi,
Imaizumi Tsutomu,
Matsuda Tadashi,
Ihle James N.,
Yoshimura Akihiko
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.5.1309
Subject(s) - biology , sh2 domain , janus kinase , sh3 domain , biochemistry , tyrosine kinase , receptor tyrosine kinase , janus kinase 2 , tyrosine phosphorylation , microbiology and biotechnology , tyrosine , proto oncogene tyrosine protein kinase src , phosphorylation , signal transduction
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.