PTP1B is a negative regulator of interleukin 4–induced STAT6 signaling

X Lu, R Malumbres, B Shields, X Jiang… - Blood, The Journal …, 2008 - ashpublications.org
X Lu, R Malumbres, B Shields, X Jiang, KA Sarosiek, Y Natkunam, T Tiganis, IS Lossos
Blood, The Journal of the American Society of Hematology, 2008ashpublications.org
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 …
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.
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