PTP1B is a negative regulator of interleukin 4-induced STAT6 signaling.
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.
Lu
Xiaoqing
X
Sylvester Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, Monash University, Victoria, Australia.
Malumbres
Raquel
R
Shields
Benjamin
B
Jiang
Xiaoyu
X
Sarosiek
Kristopher A
KA
Natkunam
Yasodha
Y
Tiganis
Tony
T
Lossos
Izidore S
IS
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D019311:Staurosporine / Q000494:pharmacology; D053634:TYK2 Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D004791:Enzyme Inhibitors; C508598:IL4 protein, human; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; C494100:Stat6 protein, mouse; D025521:Tumor Suppressor Proteins; D015847:Interleukin-4; D019869:Phosphatidylinositol 3-Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D019311:Staurosporine