title: A new protein containing an SH2 domain that inhibits JAK kinases.
abstract: 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.
authors.affiliation: Institute of Life Science, Kurume University, Aikawamachi, Japan.
authors.forename: T A
authors.initials: TA
authors.lastname: Endo
authors.forename: M
authors.initials: M
authors.lastname: Masuhara
authors.forename: M
authors.initials: M
authors.lastname: Yokouchi
authors.forename: R
authors.initials: R
authors.lastname: Suzuki
authors.forename: H
authors.initials: H
authors.lastname: Sakamoto
authors.forename: K
authors.initials: K
authors.lastname: Mitsui
authors.forename: A
authors.initials: A
authors.lastname: Matsumoto
authors.forename: S
authors.initials: S
authors.lastname: Tanimura
authors.forename: M
authors.initials: M
authors.lastname: Ohtsubo
authors.forename: H
authors.initials: H
authors.lastname: Misawa
authors.forename: T
authors.initials: T
authors.lastname: Miyazaki
authors.forename: N
authors.initials: N
authors.lastname: Leonor
authors.forename: T
authors.initials: T
authors.lastname: Taniguchi
authors.forename: T
authors.initials: T
authors.lastname: Fujita
authors.forename: Y
authors.initials: Y
authors.lastname: Kanakura
authors.forename: S
authors.initials: S
authors.lastname: Komiya
authors.forename: A
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: 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
chemical_list: 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