Abstract
AG-490 is a member of the tyrphostin family of tyrosine kinase inhibitors. While AG-490 has been considered to be a Janus kinase (JAK)2-specific inhibitor, these conclusions were primarily drawn from acute lymphoblastic leukemia cells that lack readily detectable levels of JAK3. In the present study, evidence is provided that clearly demonstrates AG-490 potently suppresses IL-2-induced T cell proliferation, a non-JAK2-dependent signal, in a dose-dependent manner in T cell lines D10 and CTLL-2. AG-490 blocked JAK3 activation and phosphorylation of its downstream counterpart substrates, STATs. Inhibition of JAK3 by AG-490 also compromised the Shc/Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways as measured by phosphorylation of Shc and extracellular signal-related kinase 1 and 2 (ERK1/2). AG-490 effectively inhibited tyrosine phosphorylation and DNA binding activities of several transcription factors including STAT1, -3, -5a, and -5b and activating protein-1 (AP-1) as judged by Western blot analysis and electrophoretic mobility shift assay. These data suggest that AG-490 is a potent inhibitor of the JAK3/STAT, JAK3/AP-1, and JAK3/MAPK pathways and their cellular consequences. Taken together, these findings support the notion that AG-490 possesses previously unrecognized clinical potential as an immunotherapeutic drug due to its inhibitory effects on T cell-derived signaling pathways.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Adaptor Proteins, Vesicular Transport*
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Binding Sites / drug effects
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Binding Sites / immunology
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Line
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DNA / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / metabolism*
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Enzyme Activation / drug effects
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Enzyme Activation / immunology
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Enzyme Inhibitors / pharmacology
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / pharmacology
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Janus Kinase 3
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Lymphocyte Activation / drug effects
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Milk Proteins*
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Phosphorylation / drug effects
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Phosphotyrosine / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / metabolism*
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Proteins / metabolism
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RNA, Messenger / metabolism
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Receptors, Interleukin-2 / biosynthesis
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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STAT5 Transcription Factor
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Shc Signaling Adaptor Proteins
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Signal Transduction / drug effects
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Signal Transduction / immunology*
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T-Lymphocytes / drug effects*
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T-Lymphocytes / enzymology*
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T-Lymphocytes / immunology
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / metabolism*
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Tyrphostins / pharmacology*
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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DNA-Binding Proteins
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Enzyme Inhibitors
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Interleukin-2
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Milk Proteins
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Proteins
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RNA, Messenger
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Receptors, Interleukin-2
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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STAT5 Transcription Factor
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Shc Signaling Adaptor Proteins
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Trans-Activators
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Tyrphostins
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alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
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Phosphotyrosine
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DNA
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Protein-Tyrosine Kinases
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Janus Kinase 3
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Calcium-Calmodulin-Dependent Protein Kinases