PMID- 10421843
OWN - NLM
STAT- MEDLINE
DCOM- 19991014
LR  - 20161124
IS  - 1356-9597 (Print)
IS  - 1356-9597 (Linking)
VI  - 4
IP  - 6
DP  - 1999 Jun
TI  - 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.
PG  - 339-51
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.
FAU - Sasaki, A
AU  - Sasaki A
AD  - Institute of Life Science, Kurume University, Aikawa-machi 2432-3 Kurume
      839-0861, Japan.
FAU - Yasukawa, H
AU  - Yasukawa H
FAU - Suzuki, A
AU  - Suzuki A
FAU - Kamizono, S
AU  - Kamizono S
FAU - Syoda, T
AU  - Syoda T
FAU - Kinjyo, I
AU  - Kinjyo I
FAU - Sasaki, M
AU  - Sasaki M
FAU - Johnston, J A
AU  - Johnston JA
FAU - Yoshimura, A
AU  - Yoshimura A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Genes Cells
JT  - Genes to cells : devoted to molecular & cellular mechanisms
JID - 9607379
RN  - 0 (Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (SOCS3 protein, human)
RN  - 0 (Suppressor of Cytokine Signaling 3 Protein)
RN  - 0 (Suppressor of Cytokine Signaling Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 2)
SB  - IM
MH  - Amino Acid Sequence
MH  - Enzyme Activation
MH  - Humans
MH  - Janus Kinase 2
MH  - Molecular Sequence Data
MH  - Phosphorylation
MH  - Protein Binding
MH  - Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism
MH  - Proteins/*metabolism
MH  - *Proto-Oncogene Proteins
MH  - *Repressor Proteins
MH  - Signal Transduction
MH  - Suppressor of Cytokine Signaling 3 Protein
MH  - Suppressor of Cytokine Signaling Proteins
MH  - *Transcription Factors
MH  - *src Homology Domains
EDAT- 1999/07/28 00:00
MHDA- 1999/07/28 00:01
CRDT- 1999/07/28 00:00
PHST- 1999/07/28 00:00 [pubmed]
PHST- 1999/07/28 00:01 [medline]
PHST- 1999/07/28 00:00 [entrez]
AID - gtc263 [pii]
PST - ppublish
SO  - Genes Cells. 1999 Jun;4(6):339-51.