The JAK‐binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop
Open accessAbstract
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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SOCS1 and SOCS3 inhibit STAT3 in a cytokine-inducible manner by binding to and inhibiting upstream JAKs.
“The suppressor of cytokine signaling (SOCS) family of proteins, especially SOCS1 and SOCS3, inhibit STAT3 in a cytokine-inducible manner by binding to and inhibiting upstream JAKs.13,14”
From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [14]
The Introduction identifies JAB as SOCS1, and the JAK-kinase Results section reports that JAB binds to and inhibits JAK2. The same Results section says CIS3 binds JAK2 weakly but did not inhibit its kinase activity in this assay. The passages do not establish inhibition of STAT3 by either protein or show that the inhibition itself is cytokine-inducible. (LLM, conf=0.88)
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- Authors
- Yasukawa, H., Misawa, H., Sakamoto, H., Masuhara, M., Sasaki, A., Wakioka, T., Ohtsuka, S., Imaizumi, T., Matsuda, T., Ihle, J. N., & Yoshimura, A.
- Affiliations
- Kurume University (JP)
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Yoshimura, Akihiko
- Venue
- The EMBO Journal
- Published
- 1999-03-01
- Volume
- 18
- Issue
- 5
- Pages
- 1309-1320
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1171221
- OpenAlex
- W2108486371
- Cited by
- 719
- References
- 1
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 9 · 2023: 14 · 2022: 6 · 2021: 17 · 2020: 13 · 2019: 25 · 2018: 15 · 2017: 27 · 2016: 17 · 2015: 20 · 2014: 29 · 2013: 30 · 2012: 35
- FWCI
- 19.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sumitomo Foundation
- Kanae Foundation for the Promotion of Medical Science
- National Heart, Lung, and Blood Institute (P01HL053749, P0 HL53749)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- jab, JAK2, Janus tyrosine kinases, kinase inhibition, activation loop, tyrosine phosphorylation, SH2 domain, cytokine signaling, tyrosine kinase inhibitors
- MeSH terms
- Suppressor of Cytokine Signaling 1 Protein, Amino Acid Sequence, Carrier Proteins, Cell Line, Enzyme Activation, Molecular Sequence Data, Mutation, Phosphopeptides, Phosphorylation, Protein Binding, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Repressor Proteins, Suppression, Genetic, Signal Transduction, Sequence Deletion, src Homology Domains, Intracellular Signaling Peptides and Proteins, Suppressor of Cytokine Signaling Proteins, Janus Kinase 2
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