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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
1999-6-29
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pubmed:abstractText |
Janus kinase 3 (JAK3) is a cytoplasmic tyrosine kinase required for T cell development and activated by cytokines that utilize the interleukin-2 (IL-2) receptor common gamma chain (gamma(c)). Genetic inactivation of JAK3 is manifested as severe combined immunodeficiency disease (SCID) in humans and mice. These findings have suggested that JAK3 represents a pharmacological target to control certain lymphoid-derived diseases. Here we provide novel evidence that AG-490 potently inhibits the autokinase activity of JAK3 and tyrosine phosphorylation and DNA binding of signal transducer and activator of transcription 5a and 5b (STAT5a/b). Similar inhibitory effects were observed with other cytokines that use gamma(c). AG-490 also inhibited IL-2-mediated proliferative growth in human T cells with an IC50) = 25 microM that was partially recoverable. Moreover, we demonstrate that this inhibitor prevented tetanus toxoid antigen-specific T cell proliferation and expansion but failed to block activation of Zap70 or p56Lck after anti-CD3 stimulation of human T cells. Taken together, these findings suggest that AG-490 inhibits the JAK3-mediated Type II signaling pathway but not the T cell receptor-derived Type I pathway and possesses therapeutic potential for T cell-derived pathologies such as graft-versus-host disease, allergy, and autoimmune disorders.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antigens,
http://linkedlifedata.com/resource/pubmed/chemical/Cytokines,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-2,
http://linkedlifedata.com/resource/pubmed/chemical/JAK3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Jak3 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Janus Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrphostins,
http://linkedlifedata.com/resource/pubmed/chemical/alpha-cyano-(3,4-dihydroxy)-N-benzyl...
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0741-5400
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
65
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
891-9
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:10380915-Animals,
pubmed-meshheading:10380915-Antigens,
pubmed-meshheading:10380915-Cell Division,
pubmed-meshheading:10380915-Cytokines,
pubmed-meshheading:10380915-DNA-Binding Proteins,
pubmed-meshheading:10380915-Enzyme Inhibitors,
pubmed-meshheading:10380915-Humans,
pubmed-meshheading:10380915-Interleukin-2,
pubmed-meshheading:10380915-Janus Kinase 3,
pubmed-meshheading:10380915-Lymphocyte Activation,
pubmed-meshheading:10380915-Mice,
pubmed-meshheading:10380915-Phosphorylation,
pubmed-meshheading:10380915-Protein-Tyrosine Kinases,
pubmed-meshheading:10380915-Signal Transduction,
pubmed-meshheading:10380915-T-Lymphocytes,
pubmed-meshheading:10380915-Transcription Factors,
pubmed-meshheading:10380915-Tyrphostins
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pubmed:year |
1999
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pubmed:articleTitle |
Tyrphostin AG-490 inhibits cytokine-mediated JAK3/STAT5a/b signal transduction and cellular proliferation of antigen-activated human T cells.
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pubmed:affiliation |
IRSP, SAIC Frederick, Frederick Cancer Research and Development Center, Maryland, USA. rkirken@farmr1.med.uth.tmc.edu
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pubmed:publicationType |
Journal Article
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