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

Xiaoqing Lu, Raquel Malumbres, Benjamin Shields, Xiaoyu Jiang, Kristopher A. Sarosiek, Yasodha Natkunam, Tony Tiganis, Izidore S. Lossos

Research output: Contribution to journalArticle

87 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4098-4108
Number of pages11
JournalBlood
Volume112
Issue number10
DOIs
StatePublished - Nov 15 2008

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Lu, X., Malumbres, R., Shields, B., Jiang, X., Sarosiek, K. A., Natkunam, Y., Tiganis, T., & Lossos, I. S. (2008). PTP1B is a negative regulator of interleukin 4-induced STAT6 signaling. Blood, 112(10), 4098-4108. https://doi.org/10.1182/blood-2008-03-148726