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

Atsuo Sasaki, Hideo Yasukawa, Asuka Suzuki, Shintaro Kamizono, Takanori Syoda, Ichiko Kinjyo, Mika Sasaki, James A. Johnston, Akihiko Yoshimura

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)339-351
Number of pages13
JournalGenes to Cells
Volume4
Issue number6
DOIs
Publication statusPublished - 1999
Externally publishedYes

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Janus Kinases
src Homology Domains
Protein-Tyrosine Kinases
Phosphotransferases
Cytokines
Proteins
Carrier Proteins
Cytokine Receptors
Cell Differentiation

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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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. / Sasaki, Atsuo; Yasukawa, Hideo; Suzuki, Asuka; Kamizono, Shintaro; Syoda, Takanori; Kinjyo, Ichiko; Sasaki, Mika; Johnston, James A.; Yoshimura, Akihiko.

In: Genes to Cells, Vol. 4, No. 6, 1999, p. 339-351.

Research output: Contribution to journalArticle

Sasaki, Atsuo ; Yasukawa, Hideo ; Suzuki, Asuka ; Kamizono, Shintaro ; Syoda, Takanori ; Kinjyo, Ichiko ; Sasaki, Mika ; Johnston, James A. ; Yoshimura, Akihiko. / 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. In: Genes to Cells. 1999 ; Vol. 4, No. 6. pp. 339-351.
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abstract = "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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T1 - 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

AU - Sasaki, Atsuo

AU - Yasukawa, Hideo

AU - Suzuki, Asuka

AU - Kamizono, Shintaro

AU - Syoda, Takanori

AU - Kinjyo, Ichiko

AU - Sasaki, Mika

AU - Johnston, James A.

AU - Yoshimura, Akihiko

PY - 1999

Y1 - 1999

N2 - 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.

AB - 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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