A new protein containing an SH2 domain that inhibits JAK kinases
Abstract
The proliferation and differentiation of cells of many lineages are regulated by secreted proteins known as cytokines. Cytokines exert their biological effect through binding to cell-surface receptors that are associated with one or more members of the JAK family of cytoplasmic tyrosine kinases. Cytokine-induced receptor dimerization leads to the activation of JAKs, rapid tyrosine-phosphorylation of the cytoplasmic domains, and subsequent recruitment of various signalling proteins, including members of the STAT family of transcription factors, to the receptor complex. Using the yeast two-hybrid system, we have now isolated a new SH2-domain-containing protein, JAB, which is a JAK-binding protein that interacts with the Jak2 tyrosine-kinase JH1 domain. JAB is structurally related to CIS, a cytokine-inducible SH2 protein. Interaction of JAB with Jak1, Jak2 or Jak3 markedly reduces their tyrosine-kinase activity and suppresses the tyrosine-phosphorylation and activation of STATs. JAB and CIS appear to function as negative regulators in the JAK signalling pathway.
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SOCS1 functions by binding directly to JAK proteins.
“Whereas SOCS1 functions by binding directly to JAK proteins, SOCS3 inhibits signaling by binding to phosphorylated tyrosine sites on the cytoplasmic domain of the receptor (19,20).”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [19]
SOCS3 inhibits signaling by binding to phosphorylated tyrosine sites on the cytoplasmic domain of the receptor.
“Whereas SOCS1 functions by binding directly to JAK proteins, SOCS3 inhibits signaling by binding to phosphorylated tyrosine sites on the cytoplasmic domain of the receptor (19,20).”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [19]
SOCS1 and SOCS3 proteins can both inhibit JAK phosphorylation of STAT, creating a negative feedback loop that attenuates cytokine signal transduction.
“SOCS1 and SOCS3 proteins can both inhibit JAK phosphorylation of STAT, thus creating a negative feedback loop that attenuates cytokine signal transduction, although the mechanisms by which they act appear to differ.”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [19]
SOCS3 inhibits JAK activity and thereby contributes to the transient activation profile of STAT3.
“The negative feedback inhibitor suppressor of cytokine signalling 3 (SOCS3) inhibits JAK activity and thereby contributes to the transient activation profile of STAT3 [3].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [3]
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References 20 · Cited by 1,408
- Authors
- Endo, T. A., Masuhara, M., Yokouchi, M., Suzuki, R., Sakamoto, H., Mitsui, K., Matsumoto, A., Tanimura, S., Ohtsubo, M., Misawa, H., Miyazaki, T., Leonor, N., Taniguchi, T., Fujita, T., Kanakura, Y., Komiya, S., & Yoshimura, A.
- Affiliations
- Kurume University (JP)
- The University of Tokyo (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Osaka University Hospital (JP)
- Corresponding author
- Yoshimura, Akihiko
- ORCID
- Venue
- Nature
- Published
- 1997-06-26
- Volume
- 387
- Issue
- 6636
- Pages
- 921-924
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1488478985
- Cited by
- 1,408
- References
- 20
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 22 · 2023: 19 · 2022: 18 · 2021: 25 · 2020: 28 · 2019: 34 · 2018: 27 · 2017: 20 · 2016: 31 · 2015: 30 · 2014: 41 · 2013: 39 · 2012: 44
- FWCI
- 47.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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
- jab, SH2 domain, JAK kinases, JAK2, JAK1, JAK3, negative regulation, STAT phosphorylation, cytokine receptors, receptor dimerization, CIS, tyrosine kinase inhibition
- MeSH terms
- Suppressor of Cytokine Signaling 1 Protein, Interleukin-6 Inhibitors, Amino Acid Sequence, Animals, Carrier Proteins, Cell Line, Cloning, Molecular, DNA-Binding Proteins, Enzyme Inhibitors, Erythropoietin, Gene Expression Regulation, Humans, Interleukin-2, Milk Proteins, Molecular Sequence Data, Phosphorylation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Repressor Proteins, Saccharomyces cerevisiae, Signal Transduction, Trans-Activators, Interleukin-6, Proto-Oncogene Proteins c-fos, Immediate-Early Proteins, Genes, Reporter, DNA, Complementary, src Homology Domains, Intracellular Signaling Peptides and Proteins, STAT3 Transcription Factor, STAT5 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice, Rats, Janus Kinase 2
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