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A THEMIS : SHP 1 complex promotes T‐cell survival
Author(s) -
Paster Wolfgang,
Bruger Annika M,
Katsch Kristin,
Grégoire Claude,
Roncagalli Romain,
Fu Guo,
Gascoigne Nicholas RJ,
Nika Konstantina,
Cohnen Andre,
Feller Stephan M,
Simister Philip C,
Molder Kelly C,
Cordoba ShaunPaul,
Dushek Omer,
Malissen Bernard,
Acuto Oreste
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201387725
Subject(s) - biology , t cell receptor , grb2 , phosphorylation , signal transducing adaptor protein , microbiology and biotechnology , mapk/erk pathway , phosphatase , t cell , genetics , immune system
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 SHP 1 and SHP 2. This complex requires the adapter GRB 2, which bridges SHP to THEMIS in a Tyr‐phosphorylation‐independent fashion. Rather, SHP 1 and THEMIS engage with the N‐ SH 3 and C‐ SH 3 domains of GRB 2, respectively, a configuration that allows GRB 2‐ SH 2 to recruit the complex onto LAT . Consistent with THEMIS ‐mediated recruitment of SHP to the TCR signalosome, THEMIS knock‐down increased TCR ‐induced CD 3‐ζ phosphorylation, Erk activation and CD 69 expression, but not LCK phosphorylation. This generalized TCR signalling increase led to augmented apoptosis, a phenotype mirrored by SHP 1 knock‐down. Remarkably, a KI mutation of LCK Ser59, previously suggested to be key in ERK ‐mediated resistance towards SHP 1 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.