A THEMIS:SHP1 complex promotes T-cell survival.

Autor: Paster W; T Cell Signalling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK wolfgang.paster@path.ox.ac.uk wolfgang.paster@meduniwien.ac.at bernardm@ciml.univ-mrs.fr oreste.acuto@path.ox.ac.uk., Bruger AM; T Cell Signalling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK., Katsch K; T Cell Signalling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK., Grégoire C; Centre d'Immunologie de Marseille-Luminy, UM2 Aix-Marseille Université, Marseille, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France., Roncagalli R; Centre d'Immunologie de Marseille-Luminy, UM2 Aix-Marseille Université, Marseille, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France., Fu G; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA., Gascoigne NR; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Nika K; T Cell Signalling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK., Cohnen A; T Cell Signalling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK., Feller SM; Biological Systems Architecture Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK Tumor Biology Unit, Institute of Molecular Medicine, ZAMED, Martin Luther University Halle-Wittenberg, Halle, Germany., Simister PC; Biological Systems Architecture Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Molder KC; T Cell Signalling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK., Cordoba SP; Molecular Immunology Group, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK., Dushek O; Molecular Immunology Group, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK., Malissen B; Centre d'Immunologie de Marseille-Luminy, UM2 Aix-Marseille Université, Marseille, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France wolfgang.paster@path.ox.ac.uk wolfgang.paster@meduniwien.ac.at bernardm@ciml.univ-mrs.fr oreste.acuto@path.ox.ac.uk., Acuto O; T Cell Signalling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK wolfgang.paster@path.ox.ac.uk wolfgang.paster@meduniwien.ac.at bernardm@ciml.univ-mrs.fr oreste.acuto@path.ox.ac.uk.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2015 Feb 03; Vol. 34 (3), pp. 393-409. Date of Electronic Publication: 2014 Dec 22.
DOI: 10.15252/embj.201387725
Abstrakt: THEMIS is critical for conventional T-cell development, but its precise molecular function remains elusive. Here, we show that THEMIS constitutively associates with the phosphatases SHP1 and SHP2. This complex requires the adapter GRB2, which bridges SHP to THEMIS in a Tyr-phosphorylation-independent fashion. Rather, SHP1 and THEMIS engage with the N-SH3 and C-SH3 domains of GRB2, respectively, a configuration that allows GRB2-SH2 to recruit the complex onto LAT. Consistent with THEMIS-mediated recruitment of SHP to the TCR signalosome, THEMIS knock-down increased TCR-induced CD3-ζ phosphorylation, Erk activation and CD69 expression, but not LCK phosphorylation. This generalized TCR signalling increase led to augmented apoptosis, a phenotype mirrored by SHP1 knock-down. Remarkably, a KI mutation of LCK Ser59, previously suggested to be key in ERK-mediated resistance towards SHP1 negative feedback, did not affect TCR signalling nor ligand discrimination in vivo. Thus, the THEMIS:SHP complex dampens early TCR signalling by a previously unknown molecular mechanism that favours T-cell survival. We discuss possible implications of this mechanism in modulating TCR output signals towards conventional T-cell development and differentiation.
(© 2014 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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