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

  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},
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.



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

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.

A new protein containing an SH2 domain that inhibits JAK kinases

A new SH2-domain-containing protein is isolated, JAB, which is a JAK-binding protein that interacts with the Jak2 tyrosine-kinase JH1 domain, and JAB and CIS appear to function as negative regulators in the JAK signalling pathway.

The CIS/JAB family: novel negative regulators of JAK signaling pathways

CIS3 and JAB directly binds to the kinase domain of JAKs, thereby inhibiting tyrosine kinase activity, suggesting that elevated expression of JAB is involved in interferon-resistance.

A novel cytokine‐inducible gene CIS encodes an SH2‐containing protein that binds to tyrosine‐phosphorylated interleukin 3 and erythropoietin receptors.

A novel gene, CIS (cytokine inducible SH2‐containing protein), which is induced in hematopoietic cells by a subset of cytokines but not by stem cell factor, granulocyte colony‐stimulating factor and IL6 is isolated.

CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation.

CIS is a feedback modulator of STAT5; its expression is induced by STAT5 and it negatively modulates STAT5 activation, indicating that CIS is a target of the JAK-STAT5 pathway of cytokine receptors.

Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL‐6 signal transduction

Although inhibition of signaling by SOCs‐1 and SOCS‐3 requires both the SH2 and N‐terminal domains, their mechanisms of action appear to be biochemically different.

A Janus kinase inhibitor, JAB, is an interferon-gamma-inducible gene and confers resistance to interferons.

The results suggest that JAB inhibits IFN signaling by blocking JAK activity, and found that IFN-resistant clones derived from LoVo cells and Daudi cells expressed high levels of JAB without stimulation, which could be, at least in part, a mechanism of IFN resistance.

Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop

The results demonstrate the critical role of phosphorylation of Y1007 in Jak2 regulation and function and demonstrate that among a variety of sites, Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions.

A family of cytokine-inducible inhibitors of signalling

Transcription of all four SOCS genes is increased rapidly in response to interleukin-6, in vitro and in vivo, suggesting they may act in a classic negative feedback loop to regulate cytokine signal transduction.