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

@article{Sasaki1999CytokineinducibleSP,
  title={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},
  author={Atsuo T. Sasaki and Hideo Yasukawa and Asuka Suzuki and Shintaro Kamizono and Takanori Syoda and Ichiko Kinjyo and Mika Sasaki and James A Johnston and Akihiko Yoshimura},
  journal={Genes to Cells},
  year={1999},
  volume={4}
}
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… 

The Pseudokinase Domain Is Required for Suppression of Basal Activity of Jak2 and Jak3 Tyrosine Kinases and for Cytokine-inducible Activation of Signal Transduction*

It is proposed that the JH2 domain contributes to both the uninduced and ligand-induced Jak-receptor complex, where it acts as a cytokine-inducible switch to regulate signal transduction.

SHP-2 Regulates SOCS-1-mediated Janus Kinase-2 Ubiquitination/Degradation Downstream of the Prolactin Receptor*

It is reported that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability.

SHP2 and SOCS3 Contribute to Tyr-759-dependent Attenuation of Interleukin-6 Signaling through gp130*

Experiments suggest, that there are two, largely distinct modes of negative regulation of gp130 activity, despite the fact that both SOCS3 and SHP2 are recruited to the same site within gp130.

SOCS3 binds specific receptor–JAK complexes to control cytokine signaling by direct kinase inhibition

The inhibitory protein SOCS3 plays a key part in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of

Negative regulation of cytokine signaling pathways.

Biochemical characterization as well as gene disruption studies indicate that JAB/SOCS1/SSI-1 is an important negative regulator of interferon gamma signaling.

Regulation of Jak2 through the Ubiquitin-Proteasome Pathway Involves Phosphorylation of Jak2 on Y1007 and Interaction with SOCS-1

It is indicated that the ubiquitin-proteasome pathway negatively regulates tyrosine-phosphorylated Jak2 in cytokine receptor signaling, which provides an additional mechanism to control activation of Jak2 and maintain cellular homeostasis.

The Janus Kinase Inhibitor, JAB/SOCS-1, Is an Interferon-γ Inducible Gene and Determines the Sensitivity to Interferons

A functional structure of JAB/SOCS-1 is defined and a mechanism for how JAB inhibits JAK kinase activity is proposed, which is indeed a “negative feedback regulator” that determine the sensitivity of cells to IFNγ.

Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3.

Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130.

Data suggest that the mechanism by which SOCS-3 inhibited signaling in cells transfected with a chimeric receptor containing the wild-type gp130 intracellular domain depends on recruitment to the phosphorylated gp130 receptor, and that some of the negative regulatory roles previously attributed to the tyrosine phosphatase SHP-2 might in fact be caused by the action of SOCS.

SOCS3 Exerts Its Inhibitory Function on Interleukin-6 Signal Transduction through the SHP2 Recruitment Site of gp130*

The interplay of two inhibitors in the signal transduction pathway of interleukin-6 is analyzed and it is demonstrated that the tyrosine phosphatase SHP2 and SOCS3 do not act independently but are functionally linked.
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References

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It is demonstrated that JAB specifically binds to the tyrosine residue (Y1007) in the activation loop of JAK2, whose phosphorylation is required for activation of kinase activity.

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