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Blood, 15 November 2008, Vol. 112, No. 10, pp. 4098-4108. Prepublished online as a Blood First Edition Paper on August 20, 2008; DOI 10.1182/blood-2008-03-148726. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-03-148726v1 112/10/4098    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lu, X. Articles by Lossos, I. S. Search for Related Content PubMed PubMed Citation Articles by Lu, X. Articles by Lossos, I. S. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY PTP1B is a negative regulator of interleukin 4–induced STAT6 signaling Xiaoqing Lu1, Raquel Malumbres1, Benjamin Shields2, Xiaoyu Jiang1, Kristopher A. Sarosiek1, Yasodha Natkunam3, Tony Tiganis2, and Izidore S. Lossos1,4 1 Sylvester Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, and 2 Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia; 3 Department of Pathology, Stanford University, CA; and 4 Department of Molecular and Cellular Pharmacology, University of Miami, FL 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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