The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop

Hideo Yasukawa, Hiroyuki Misawa, Hiroshi Sakamoto, Masaaki Masuhara, Atsuo Sasaki, Toru Wakioka, Satoshi Ohtsuka, Tsutomu Imaizumi, Tadashi Matsuda, James N. Ihle, Akihiko Yoshimura

Research output: Contribution to journalArticle

563 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1309-1320
Number of pages12
JournalEMBO Journal
Volume18
Issue number5
Publication statusPublished - 1999 Mar 1
Externally publishedYes

Fingerprint

Janus Kinases
Protein Binding
Protein-Tyrosine Kinases
Carrier Proteins
Chemical activation
Phosphotransferases
Amino Acids
Phosphorylation
Cytokine Receptors
src Homology Domains
Cell growth
Tyrosine
Cell Differentiation
Thermodynamic properties
Association reactions
Growth
Proteins

Keywords

  • Activation loop
  • CIS
  • JAB
  • JAK
  • SH2 domain

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Yasukawa, H., Misawa, H., Sakamoto, H., Masuhara, M., Sasaki, A., Wakioka, T., ... Yoshimura, A. (1999). The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO Journal, 18(5), 1309-1320.

The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. / Yasukawa, Hideo; Misawa, Hiroyuki; Sakamoto, Hiroshi; Masuhara, Masaaki; Sasaki, Atsuo; Wakioka, Toru; Ohtsuka, Satoshi; Imaizumi, Tsutomu; Matsuda, Tadashi; Ihle, James N.; Yoshimura, Akihiko.

In: EMBO Journal, Vol. 18, No. 5, 01.03.1999, p. 1309-1320.

Research output: Contribution to journalArticle

Yasukawa, H, Misawa, H, Sakamoto, H, Masuhara, M, Sasaki, A, Wakioka, T, Ohtsuka, S, Imaizumi, T, Matsuda, T, Ihle, JN & Yoshimura, A 1999, 'The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop', EMBO Journal, vol. 18, no. 5, pp. 1309-1320.
Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T et al. The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO Journal. 1999 Mar 1;18(5):1309-1320.
Yasukawa, Hideo ; Misawa, Hiroyuki ; Sakamoto, Hiroshi ; Masuhara, Masaaki ; Sasaki, Atsuo ; Wakioka, Toru ; Ohtsuka, Satoshi ; Imaizumi, Tsutomu ; Matsuda, Tadashi ; Ihle, James N. ; Yoshimura, Akihiko. / The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. In: EMBO Journal. 1999 ; Vol. 18, No. 5. pp. 1309-1320.
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