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2015 ; 34
(3
): 393-409
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A THEMIS:SHP1 complex promotes T-cell survival
#MMPMID25535246
Paster W
; Bruger AM
; Katsch K
; Grégoire C
; Roncagalli R
; Fu G
; Gascoigne NR
; Nika K
; Cohnen A
; Feller SM
; Simister PC
; Molder KC
; Cordoba SP
; Dushek O
; Malissen B
; Acuto O
EMBO J
2015[Feb]; 34
(3
): 393-409
PMID25535246
show ga
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-? 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.
|*Signal Transduction
[MESH]
|Animals
[MESH]
|CD3 Complex/genetics/metabolism
[MESH]
|Cell Differentiation/genetics
[MESH]
|Cell Survival/genetics
[MESH]
|GRB2 Adaptor Protein/genetics/metabolism
[MESH]
|Humans
[MESH]
|Intercellular Signaling Peptides and Proteins
[MESH]
|Intracellular Signaling Peptides and Proteins/genetics/*metabolism
[MESH]
|Jurkat Cells
[MESH]
|Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics/metabolism
[MESH]
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