title: A THEMIS:SHP1 complex promotes T-cell survival.
abstract: 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.
authors.affiliation: 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.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Paster
authors.affiliation: T Cell Signalling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Annika M
authors.initials: AM
authors.lastname: Bruger
authors.affiliation: T Cell Signalling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Kristin
authors.initials: K
authors.lastname: Katsch
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, UM2 Aix-Marseille Université, Marseille, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Grégoire
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, UM2 Aix-Marseille Université, Marseille, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Roncagalli
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Guo
authors.initials: G
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Nicholas R J
authors.initials: NR
authors.lastname: Gascoigne
authors.affiliation: T Cell Signalling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Nika
authors.affiliation: T Cell Signalling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Andre
authors.initials: A
authors.lastname: Cohnen
authors.affiliation: 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.
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Feller
authors.affiliation: Biological Systems Architecture Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Simister
authors.affiliation: T Cell Signalling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Molder
authors.affiliation: Molecular Immunology Group, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Shaun-Paul
authors.initials: SP
authors.lastname: Cordoba
authors.affiliation: Molecular Immunology Group, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Omer
authors.initials: O
authors.lastname: Dushek
authors.affiliation: 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.
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.affiliation: 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.
authors.forename: Oreste
authors.initials: O
authors.lastname: Acuto
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D017252:CD3 Complex; C485468:Cd3e protein, mouse; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C544192:themis protein, mouse; C557796:thymocyte-expressed molecule involved in selection, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C516725:Ptpn11 protein, mouse
keywords: SHP1; TCR; THEMIS; apoptosis; negative feedback