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 Lossos

Research output: Contribution to journalArticle

81 Citations (Scopus)

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

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Interleukin-4
Phosphorylation
Cells
Substrates
Phosphatidylinositol 3-Kinase
Neoplastic Processes
Staurosporine
Lymphoma, Large B-Cell, Diffuse
Protein Stability
Tyrosine

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Lu, X., Malumbres, R., Shields, B., Jiang, X., Sarosiek, K. A., Natkunam, Y., ... Lossos, I. (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

PTP1B is a negative regulator of interleukin 4-induced STAT6 signaling. / Lu, Xiaoqing; Malumbres, Raquel; Shields, Benjamin; Jiang, Xiaoyu; Sarosiek, Kristopher A.; Natkunam, Yasodha; Tiganis, Tony; Lossos, Izidore.

In: Blood, Vol. 112, No. 10, 15.11.2008, p. 4098-4108.

Research output: Contribution to journalArticle

Lu, X, Malumbres, R, Shields, B, Jiang, X, Sarosiek, KA, Natkunam, Y, Tiganis, T & Lossos, I 2008, 'PTP1B is a negative regulator of interleukin 4-induced STAT6 signaling', Blood, vol. 112, no. 10, pp. 4098-4108. https://doi.org/10.1182/blood-2008-03-148726
Lu X, Malumbres R, Shields B, Jiang X, Sarosiek KA, Natkunam Y et al. PTP1B is a negative regulator of interleukin 4-induced STAT6 signaling. Blood. 2008 Nov 15;112(10):4098-4108. https://doi.org/10.1182/blood-2008-03-148726
Lu, Xiaoqing ; Malumbres, Raquel ; Shields, Benjamin ; Jiang, Xiaoyu ; Sarosiek, Kristopher A. ; Natkunam, Yasodha ; Tiganis, Tony ; Lossos, Izidore. / PTP1B is a negative regulator of interleukin 4-induced STAT6 signaling. In: Blood. 2008 ; Vol. 112, No. 10. pp. 4098-4108.
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