PXD054302

PXD054302 is an original dataset announced via ProteomeXchange.

Title	Development of a Peptide Inhibitor Targeting the C-SH2 Domain of the SHP2 Phosphatase
Description	Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) has important cellular functions in mediating signal transduction downstream of receptor tyrosine kinases and immune cell receptors. In T cells, SHP2 is a key regulator of signalling pathways downstream of the checkpoint receptor programmed cell death protein 1 (PD-1) that suppresses T cell activation, and of the T cell receptor (TCR) that promotes T cell activation. SHP2 contains two SH2 domains: the N-SH2 and C-SH2 domains. Here, we describe a new approach for the chemical targeting of SHP2 by developing a peptide inhibitor, containing a non-hydrolysable phosphotyrosine (pTyr) mimetic, which selectively binds to the C-SH2 domain of SHP2. We found that incorporation of the pTyr mimetic L-O-malonyltyrosine (L-OMT) displayed robust binding affinity to the C-SH2 domain, while the widely used pTyr mimetic phosphonodifluoromethyl phenylalanine (F2Pmp) abolished binding, showing that the use of pTyr mimetics for SH2 domains is case dependent. Our C-SH2 inhibitor peptide (CSIP) impedes SHP2 activation and inhibits SHP2 phosphatase activity in vitro. CSIP is stable, cell permeable and non-cytotoxic in a model T cell line (Jurkat), in which it displays cellular activity in modulating T cell activation. As such, CSIP is a powerful chemical tool to study SHP2, in particular the role of its C-SH2 domain, in cellular contexts. CSIP enriches the toolbox of inhibitors with different modes of action to study SHP2.
HostingRepository	PRIDE
AnnounceDate	2025-05-09
AnnouncementXML	Submission_2025-05-09_06:59:08.278.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Julian Bender
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-28 00:49:06	ID requested
⏵ 1	2025-05-09 06:59:08	announced

10.1002/CBIC.202400938;

submitter keyword: pulldown,SHP2, inhibitor, chemical biology, C-SH2 Domain

Bettina Warscheid
contact affiliation	Chair of Biochemistry II, Theodor Boveri-Institute, Biocenter, University of Würzburg, Würzburg, Germany
contact email	bettina.warscheid@uni-wuerzburg.de
lab head
Julian Bender
contact affiliation	University of Wuerzburg Chair of Biochemistry II Am Hubland 97074 Würzburg
contact email	julian.bender@uni-wuerzburg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD054302
     1. Label: PRIDE project
     2. Name: Development of a Peptide Inhibitor Targeting the C-SH2 Domain of the SHP2 Phosphatase