Cytokine‐inducible SH2 protein‐3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N‐terminal kinase inhibitory region as well as SH2 domain
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Background: The Janus family of protein tyrosine kinases (JAKs) regulate cellular processes involved in cell growth, differentiation and transformation through their association with cytokine receptors. We have recently identified the JAK‐binding protein, JAB that inhibits various cytokine‐dependent JAK signalling pathways. JAB inhibits JAK2 tyrosine kinase activity by binding to the kinase domain (JH1 domain) through the N‐terminal kinase inhibitory region (KIR) and the SH2 domain. The SH2 domain of JAB has been shown to bind to the phosphorylated Y1007 in the activation loop of JH1. We also identified another JAK‐binding protein, CIS3 (cytokine‐inducible SH2‐protein 3, or SOCS3) that inhibits signalling of various cytokines. However, the mechanism of JAK signal inhibition by CIS3 has not been clarified. Results: We showed that endogenous CIS3 bound to JAK2 in intact cells. The CIS3‐SH2 domain bound to the phosphorylated Y1007 of JH1, and inhibited tyrosine kinase activity through the N‐terminal KIR. Therefore, CIS3 and JAB inhibit JAK2 tyrosine kinase activity by an essentially similar mechanism. However, we found that the affinity of the SH2 domain of CIS3 to Y1007 was weaker than that of JAB. In contrast, the KIR of CIS3 showed stronger potential for both binding to JH1 and inhibition of JAK kinase activity than that of JAB. Consistent with this notion, chimeras containing CIS3‐KIR and JAB‐SH2 domain inhibited JAK2 kinase activity more efficiently than the wild‐type CIS3 or JAB. Conclusion: CIS3 inhibits JAK2 kinase activity by binding to the activation loop through the SH2 domain, and KIR is necessary for kinase inhibition. Although the inhibitory mechanism by CIS3 is similar to that by JAB, the contributions of the SH2 domain and KIR for binding are different between JAB and CIS3. Our study defined the inhibitory mechanism of CIS3 and provides a useful information for creating a novel tyrosine kinase inhibitor.
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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 [13]
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SOCS2 Can Enhance Interleukin-2 (IL-2) and IL-3 Signaling by Accelerating SOCS3 Degradation
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Self-citationTGF-β–induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis
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Self-citationEpstein-Barr Virus-Induced Changes in B-Lymphocyte Gene Expression
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Autophosphorylation of JAK2 on Tyrosines 221 and 570 Regulates Its Activity
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The roles of SOCS 3 and STAT 3 in bacterial infection and inflammatory diseases
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Adiponectin Inhibits Pro-inflammatory Signaling in Human Macrophages Independent of Interleukin-10
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The Role and Therapeutic Targeting of JAK/STAT Signaling in Glioblastoma
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Self-citationJak-Stat Signaling Induced by Interleukin-6 Family Cytokines in Hepatocellular Carcinoma
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Self-citationHeat stress abatement during the dry period influences prolactin signaling in lymphocytes
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Negative Regulators of Cytokine Signaling
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Heat Stress and Animal Productivity
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- Authors
- Sasaki, A., Yasukawa, H., Suzuki, A., Kamizono, S., Syoda, T., Kinjyo, I., Sasaki, M., Johnston, J. A., & Yoshimura, A.
- Affiliations
- Kurume University (JP)
- Corresponding author
- Yoshimura, Akihiko
- Venue
- Genes to Cells
- Publisher
- Wiley
- Published
- 1999-06
- Volume
- 4
- Issue
- 6
- Pages
- 339-351
- ISSN
- 1356-9597 (ISSN-L)
- 1365-2443
- OpenAlex
- W2008295144
- Cited by
- 398
- References
- 28
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 8 · 2023: 11 · 2022: 13 · 2021: 13 · 2020: 13 · 2019: 17 · 2018: 15 · 2017: 15 · 2016: 8 · 2015: 17 · 2014: 19 · 2013: 18 · 2012: 29
- FWCI
- 5.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes to Cells (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Naito Foundation
- Sumitomo Foundation
- Kanae Foundation for the Promotion of Medical Science
- 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 › Receptor Mechanisms and Signaling
- Keywords
- SOCS3, JAK2, SH2 domain, jab, cytokine signaling, protein tyrosine kinase inhibitors, fusion protein
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Amino Acid Sequence, Enzyme Activation, Humans, Molecular Sequence Data, Phosphorylation, Protein Binding, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Repressor Proteins, Transcription Factors, Signal Transduction, src Homology Domains, Suppressor of Cytokine Signaling Proteins, Janus Kinase 2
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