Submitted March 28, 2008
Accepted August 7, 2008
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, and Izidore S. Lossos*
The Sylvester Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of Miami, Miami
Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia
Department of Pathology, Stanford University, Stanford
Department of Molecular and Cellular Pharmacology, University of Miami, Miami
* Corresponding author; email: ilossos{at}med.miami.edu.
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 cytoplasmiic substrate for PTP1B. Over-expression of PTP1B led to STAT6 dephosphorylation and the suppression of STAT6 transcriptional activity while PTP1B knockdown or deficiency augmented IL4-induced STAT6 signaling. Pre-treatment 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 (IL4) inducible manner. We delineate a new negative regulatory loop of IL4-JAK-STAT6 signaling. We demonstrate that IL4 induces PTP1B mRNA expression in a phosphatidylinositol 3-kinase-dependent manner and enhances PTP1B protein stability to suppress IL4-induced STAT6 signaling. Finally, we show that PTP1B expression may be preferentially elevated in activated B-cell-like diffuse large B-cell lymphomas (DLBCL). These observations identify a novel regulatory loop for the regulation of IL4-induced STAT6 signaling that may have important implications in both neoplastic and inflammatory processes.
