Abstract
Although Jak kinases are essential for initiating cytokine signaling, the role of other nonreceptor tyrosine kinases in this process remains unclear. We have examined the role of Fes in IL-4 signaling. Examination of Jak1-deficient cell lines demonstrates that Jak1 is required for the activation of Fes by IL-4. Experiments studying signaling molecules activated by IL-4 receptor suggest that IL-4 signaling can be subdivided into Fes-dependent and Fes-independent pathways. Overexpression of kinase-inactive Fes blocks the IL-4 activation of insulin receptor substrate-2, but not STAT6. Fes appears to be a downstream kinase from Jak1/Jak3 in this process. Further examination of downstream signaling demonstrates that kinase-inactive Fes inhibits the recruitment of phosphoinositide 3-kinase to the activated IL-4 receptor complex and decreases the activation of p70(S6k) kinase in response to IL-4. This inhibition correlates with a decrease in IL-4-induced proliferation. In contrast, mutant Fes does not inhibit the activation of Akt by IL-4. These data demonstrate that signaling pathways activated by IL-4 require different tyrosine kinases. This differential requirement predicts that specific kinase inhibitors may permit the disruption of specific IL-4-induced functions.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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B-Lymphocytes / cytology*
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B-Lymphocytes / enzymology
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B-Lymphocytes / metabolism
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Cell Division / genetics
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Cell Line
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Enzyme Activation / genetics
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Humans
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Insulin Receptor Substrate Proteins
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Interleukin-4 / physiology*
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Intracellular Signaling Peptides and Proteins
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Janus Kinase 1
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Lymphocyte Activation / genetics
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Mice
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Mutagenesis, Site-Directed
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / metabolism*
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Phosphorylation
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Protein Serine-Threonine Kinases*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Protein-Tyrosine Kinases / physiology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-fes
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Receptor, Insulin / metabolism*
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Ribosomal Protein S6 Kinases / antagonists & inhibitors
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Ribosomal Protein S6 Kinases / metabolism
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Signal Transduction / genetics
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Tumor Cells, Cultured
Substances
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IRS2 protein, human
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Irs2 protein, mouse
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoproteins
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Proto-Oncogene Proteins
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Interleukin-4
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Protein-Tyrosine Kinases
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Receptor, Insulin
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FES protein, human
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Fes protein, mouse
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JAK1 protein, human
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Jak1 protein, mouse
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Janus Kinase 1
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Proto-Oncogene Proteins c-fes
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases