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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Carrier Proteins / analysis*
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Carrier Proteins / chemistry
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Carrier Proteins / genetics
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Carrier Proteins / physiology
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Cell Line
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Cloning, Molecular
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DNA, Complementary
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DNA-Binding Proteins / genetics
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Enzyme Inhibitors / analysis*
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Erythropoietin / antagonists & inhibitors
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Erythropoietin / physiology
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Gene Expression Regulation
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Genes, Reporter
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Humans
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Immediate-Early Proteins / chemistry
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Immediate-Early Proteins / physiology
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / physiology
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Interleukin-6 / antagonists & inhibitors
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Interleukin-6 / physiology
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Intracellular Signaling Peptides and Proteins*
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Janus Kinase 2
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Mice
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Milk Proteins*
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Molecular Sequence Data
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Phosphorylation
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins*
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Rats
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Recombinant Fusion Proteins / genetics
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Repressor Proteins*
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STAT3 Transcription Factor
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STAT5 Transcription Factor
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Saccharomyces cerevisiae
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Signal Transduction*
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / genetics
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src Homology Domains*
Substances
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Carrier Proteins
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DNA, Complementary
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DNA-Binding Proteins
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Enzyme Inhibitors
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Immediate-Early Proteins
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Interleukin-2
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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Milk Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-fos
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Recombinant Fusion Proteins
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Repressor Proteins
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SOCS1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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STAT5 Transcription Factor
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Socs1 protein, mouse
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Socs1 protein, rat
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Stat3 protein, mouse
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Stat3 protein, rat
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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cytokine inducible SH2-containing protein
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Erythropoietin
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Jak2 protein, mouse
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Jak2 protein, rat
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Janus Kinase 2
Associated data
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GENBANK/AB000676
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GENBANK/AB000677