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

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. IntroductionInterleukin 4 (IL-4) is a type I cytokine that has an important role in the regulation of Th2 cells and B cells during an immune response. IL-4 regulates cellular differentiation, proliferation, and apoptosis and plays an important role in the pathogenesis of allergic and autoimmune diseases. 1,2 Furthermore, recent studies have suggested that IL-4 signaling may have an important role in neoplastic diseases. IL-4 may affect malignant cells and can elicit potent antitumor activity against carcinoma and lymphoma cell lines in vitro and in animal models. [3][4][5][6] We have recently demonstrated qualitatively different IL-4 effects on gene expression, cell proliferation, and intracellular signaling in germinal center B-cell (GCB)-like versus activated B-cell (ABC)-like diffuse large B-cell lymphomas (DLBCLs). 7 Further, our preliminary data have suggested that IL-4 may enhance chemotherapy and complementdependent rituximab-mediated cytotoxicities in GCB-like but not in ABC-like DLBCLs. 8 The pleiotropic but specific effects of IL-4 on different cell types result from the activation of distinct signaling pathways that are tightly regulated. 1 IL-4 signaling is initiated when the cytokine binds its cell surface receptor activating receptor-associated Janusactivated protein kinases (JAKs) that phosphorylate specific tyrosine residues in the IL-4R␣ chain. This is followed by recruitment and phosphorylation of signal transducer and activator of transcription 6 (STAT6) and insulin receptor substance-2 (IRS-2), and activation of phosphatidylin...

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“…Moreover, our ChIP-seq data (supplemental Tables S2 and S3) revealed robust recruitment of GR and RNAPII to the PTPN1 locus. PTPN1 is a direct target of the STAT family that represses STAT-dependent responses to cytokines, including the asthma-associated cytokine, IL4 (11,81). We thus speculate that GR cooperatively regulates negative feedback responses to diverse inflammatory signals, providing a general mechanistic explanation for the broad potency of GCbased therapies in treating a multitude of immune-mediated diseases.…”

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“…S4). Stat5 is also a substrate for Ptpn1, and Ptpn1 deficiency increases Stat6 phosphorylation in B cells (20,21). Additionally, Ptpn1-deficient mice suffer from systemic inflammation, increased leukocyte migration, and is a potential molecule in regulating the allergic response (22).…”

PTB-associated Splicing Factor (PSF) Functions as a Repressor of STAT6-mediated Igϵ Gene Transcription by Recruitment of HDAC1

“…Recently, Nigam et al (26) have observed that Although STAT6 activation in response to IL-4 and IL-13 has been well documented, the molecular mechanisms responsible for the termination of STAT6 signaling are largely unknown. Recently, protein-tyrosine phosphatases (PTP) have been shown to dephosphorylate STAT6 and act as negative regulators of IL-4/STAT6 signaling (27). STAT6 responses are also negatively regulated by SOCS1 (28).…”