| Autor: |
Lu X; Sylvester Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, Monash University, Victoria, Australia., Malumbres R, Shields B, Jiang X, Sarosiek KA, Natkunam Y, Tiganis T, Lossos IS |
| Jazyk: |
angličtina |
| Zdroj: |
Blood [Blood] 2008 Nov 15; Vol. 112 (10), pp. 4098-108. Date of Electronic Publication: 2008 Aug 20. |
| DOI: |
10.1182/blood-2008-03-148726 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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