PXD001410

PXD001410 is an original dataset announced via ProteomeXchange.

Title	A Themis:SHP complex promotes T cell survival
Description	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 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. Coherent with THEMIS-mediated recruitment of SHP to the TCR signalosome, THEMIS knockdown increased TCR-induced TCR- phosphorylation, Erk activation and CD69 expression, however not Lck phosphorylation. This generalized TCR signalling increase led to augmented apoptosis, a phenotype mirrored by SHP-1 knockdown. 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, THEMIS:SHP complex dampens early TCR signalling by a previously unknown molecular mechanism that favors T cell survival. We discuss possible implications of this mechanism in modulating TCR output signals towards conventional T cell development and differentiation.
HostingRepository	PRIDE
AnnounceDate	2015-01-07
AnnouncementXML	Submission_2015-01-07_02:02:06.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kristin Katsch
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	deamidated residue; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2014-10-17 06:55:35	ID requested
⏵ 1	2015-01-07 02:02:08	announced

Paster W, Bruger AM, Katsch K, Gr, é, goire 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, A THEMIS:SHP1 complex promotes T-cell survival. EMBO J, 34(3):393-409(2015) [pubmed]

curator keyword: Biomedical

submitter keyword: TCR, Themis, SHP1, negative feedback, apoptosis

Professor Oreste Acuto
contact affiliation	Sir William Dunn School of Pathology, Molecular Immunology Group, University of Oxford, UK
contact email	oreste.acuto@path.ox.ac.uk
lab head
Kristin Katsch
contact affiliation	University of Oxford
contact email	kristin.katsch@path.ox.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2015/01/PXD001410

PRIDE project URI

• PRIDE
  1. PXD001410
     1. Label: PRIDE project
     2. Name: A Themis:SHP complex promotes T cell survival