Abstract
Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed enzyme shown to negatively regulate multiple tyrosine phosphorylation-dependent signaling pathways. PTP1B can modulate cytokine signaling pathways by dephosphorylating JAK2, TYK2, and STAT5a/b. Herein, we report that phosphorylated STAT6 may serve as a cytoplasmic substrate for PTP1B. Overexpression of PTP1B led to STAT6 dephosphorylation and the suppression of STAT6 transcriptional activity, whereas PTP1B knockdown or deficiency augmented IL-4-induced STAT6 signaling. Pretreatment of these cells with the PTK inhibitor staurosporine led to sustained STAT6 phosphorylation consistent with STAT6 serving as a direct substrate of PTP1B. Furthermore, PTP1B-D181A "substrate-trapping" mutants formed stable complexes with phosphorylated STAT6 in a cellular context and endogenous PTP1B and STAT6 interacted in an interleukin 4 (IL-4)-inducible manner. We delineate a new negative regulatory loop of IL-4-JAK-STAT6 signaling. We demonstrate that IL-4 induces PTP1B mRNA expression in a phosphatidylinositol 3-kinase-dependent manner and enhances PTP1B protein stability to suppress IL-4-induced STAT6 signaling. Finally, we show that PTP1B expression may be preferentially elevated in activated B cell-like diffuse large B-cell lymphomas. These observations identify a novel regulatory loop for the regulation of IL-4-induced STAT6 signaling that may have important implications in both neoplastic and inflammatory processes.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / genetics
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Gene Expression Regulation, Enzymologic / immunology
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HeLa Cells
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Humans
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / metabolism
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Interleukin-4 / metabolism*
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Interleukin-4 / pharmacology
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Lymphoma, Large B-Cell, Diffuse / genetics
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Lymphoma, Large B-Cell, Diffuse / immunology
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Lymphoma, Large B-Cell, Diffuse / metabolism
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Mice
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Mice, Knockout
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Mutation, Missense
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / immunology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / biosynthesis*
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / immunology
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / immunology
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STAT5 Transcription Factor / metabolism
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STAT6 Transcription Factor / genetics
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STAT6 Transcription Factor / immunology
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STAT6 Transcription Factor / metabolism*
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Signal Transduction / physiology*
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Staurosporine / pharmacology
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TYK2 Kinase / genetics
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TYK2 Kinase / immunology
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TYK2 Kinase / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / immunology
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Tumor Suppressor Proteins / metabolism
Substances
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Enzyme Inhibitors
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IL4 protein, human
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RNA, Messenger
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STAT5 Transcription Factor
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STAT5A protein, human
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STAT5B protein, human
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STAT6 Transcription Factor
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STAT6 protein, human
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Stat5a protein, mouse
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Stat5b protein, mouse
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Stat6 protein, mouse
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Tumor Suppressor Proteins
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Interleukin-4
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Phosphatidylinositol 3-Kinases
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TYK2 Kinase
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TYK2 protein, human
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Tyk2 protein, mouse
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PTPN1 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Ptpn1 protein, mouse
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Staurosporine