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Beta-catenin inhibits T cell activation by selective interference with linker for activation of T cells-phospholipase C-?1 phosphorylation.

ABSTRACT: Despite the defined function of the ?-catenin pathway in thymocytes, its functional role in peripheral T cells is poorly understood. We report that in a mouse model, ?-catenin protein is constitutively degraded in peripheral T cells. Introduction of stabilized ?-catenin into primary T cells inhibited proliferation and cytokine secretion after TCR stimulation and blunted effector cell differentiation. Functional and biochemical studies revealed that ?-catenin selectively inhibited linker for activation of T cells phosphorylation on tyrosine 136, which was associated with defective phospholipase C-?1 phosphorylation and calcium signaling but normal ERK activation. Our findings indicate that ?-catenin negatively regulates T cell activation by a previously undescribed mechanism and suggest that conditions under which ?-catenin might be inducibly stabilized in vivo would be inhibitory for T cell-based immunity.

SUBMITTER: Driessens G

PROVIDER: S-EPMC4888792 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Beta-catenin inhibits T cell activation by selective interference with linker for activation of T cells-phospholipase C-γ1 phosphorylation.

Driessens Gregory G Zheng Yan Y Locke Frederick F Cannon Judy L JL Gounari Fotini F Gajewski Thomas F TF

Journal of immunology (Baltimore, Md. : 1950) 20101213 2

Despite the defined function of the β-catenin pathway in thymocytes, its functional role in peripheral T cells is poorly understood. We report that in a mouse model, β-catenin protein is constitutively degraded in peripheral T cells. Introduction of stabilized β-catenin into primary T cells inhibited proliferation and cytokine secretion after TCR stimulation and blunted effector cell differentiation. Functional and biochemical studies revealed that β-catenin selectively inhibited linker for acti ...[more]

PMID: 21149602

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Project description:Aberrant CTNNB1 signaling is one of the fundamental processes in cancers, especially colorectal cancer (CRC). Here, we reported that TRAF6, an E3 ubiquitin ligase important for inflammatory signaling, inhibited epithelial-mesenchymal transition (EMT) and CRC metastasis through driving a selective autophagic CTNNB1 degradation machinery. Mechanistically, TRAF6 interacted with MAP1LC3B/LC3B through its LC3-interacting region 'YxxL' and catalyzed K63-linked polyubiquitination of LC3B. The K63-linked ubiquitination of LC3B promoted the formation of the LC3B-ATG7 complex and was critical to the subsequent recognition of CTNNB1 by LC3B for the selective autophagic degradation. However, TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling. Clinically, decreased expression of TRAF6 was associated with elevated GSK3B protein levels and activity and reduced overall survival in CRC patients. Pharmacological inhibition of GSK3B activity stabilized the TRAF6 protein, promoted CTNNB1 degradation, and effectively suppressed EMT and CRC metastasis. Thus, targeting TRAF6 and its pathway may be meaningful for treating advanced CRC. Abbreviations: AMBRA1: autophagy and beclin 1 regulator 1; AOM: azoxymethane; ATG5: autophagy related 5; ATG7: autophagy related 7; Baf A1: bafilomycin A1; BECN1: beclin 1; CoIP: co-immunoprecipitation; CQ: chloroquine; CRC: colorectal cancer; CTNNB1/β-catenin: catenin beta 1; DSS: dextran sodium sulfate; EMT: epithelial-mesenchymal transition; FBS: fetal bovine serum; GFP: green fluorescent protein; GSK3B/GSK3β: glycogen synthase kinase 3 beta; IgG: Immunoglobulin G; IHC: immunohistochemistry; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; RFP: red fluorescent protein; RT: room temperature; shRNA: short hairpin RNA; siRNA: small interfering RNA; TRAF6: TNF receptor-associated factor 6; WT: wild-type; ZEB1: zinc finger E-box binding homeobox 1.

Dataset Information

Beta-catenin inhibits T cell activation by selective interference with linker for activation of T cells-phospholipase C-?1 phosphorylation.

Publications

Beta-catenin inhibits T cell activation by selective interference with linker for activation of T cells-phospholipase C-γ1 phosphorylation.

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