A new protein containing an SH2 domain that inhibits JAK kinases.
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.
Endo
T A
TA
Institute of Life Science, Kurume University, Aikawamachi, Japan.
Masuhara
M
M
Yokouchi
M
M
Suzuki
R
R
Sakamoto
H
H
Mitsui
K
K
Matsumoto
A
A
Tanimura
S
S
Ohtsubo
M
M
Misawa
H
H
Miyazaki
T
T
Leonor
N
N
Taniguchi
T
T
Fujita
T
T
Kanakura
Y
Y
Komiya
S
S
Yoshimura
A
A
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis* / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics; D004791:Enzyme Inhibitors / Q000032:analysis*; D004921:Erythropoietin / Q000037:antagonists & inhibitors / Q000502:physiology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000502:physiology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D051379:Mice; D008894:Milk Proteins; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D012441:Saccharomyces cerevisiae; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000235:genetics; D018909:src Homology Domains; D000093242:Interleukin-6 Inhibitors
D002352:Carrier Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D004921:Erythropoietin; D017874:Immediate-Early Proteins; D007376:Interleukin-2; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D008894:Milk Proteins; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D000093242:Interleukin-6 Inhibitors; C108944:SOCS1 protein, human; C494086:STAT3 protein, human; C491590:Socs1 protein, mouse; C491589:Socs1 protein, rat; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat