PXD073482-1

PXD073482 is an original dataset announced via ProteomeXchange.

Title	HX-MS study of SHP2, WT and 2 phosphomimic mutants
Description	SHP2 is a phosphatase and a critical mediator of receptor tyrosine kinase (RTK)-driven RAS/mitogen-activated protein kinase (MAPK) signaling. Despite promising preclinical data, SHP2 inhibitors have shown minimal clinical efficacy, with no defined clinical mechanisms of primary resistance. Here, we elucidate phosphorylation of SHP2 at tyrosine 62 (pY62) as a hotspot phosphorylation site in the proteome and RTK-driven tumor types in patients. We demonstrate that SRC family kinases directly phosphorylate SHP2 at Y62, downstream of but not directly phosphorylated by RTKs. Using biochemical and biophysical analyses, we show that SHP2Y62D enforces an open, active conformation, resulting in constitutive phosphatase activation that is sufficient to activate MAPK signaling and confer resistance to allosteric SHP2 inhibitors. These findings establish that SHP2 pY62 is a phosphorylation hotspot phenocopying mutational activation, a mechanism of primary resistance to SHP2 inhibitors, and a cancer drug target distinct from wildtype SHP2.
HostingRepository	PRIDE
AnnounceDate	2026-01-23
AnnouncementXML	Submission_2026-01-23_14:44:48.844.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Malcolm Wells
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	maXis

Revision	Datetime	Status	ChangeLog Entry
0	2026-01-23 13:53:33	ID requested
⏵ 1	2026-01-23 14:44:49	announced

Karunaraj P, Scheele R, Wells ML, Rathod R, Gokulu IS, Abrahamson S, Taylor L, Chowdhury L, Kazmi A, Song W, Hornbeck P, Li J, Glasgow A, Vasan N, A Hotspot Phosphorylation Site on SHP2 Drives Oncoprotein Activation and Drug Resistance. Res Sq, ():(2025) [pubmed]

10.21203/rs.3.rs-7032881/v1;

submitter keyword: Human, HX-MS, SHP2

Anum Glasgow
contact affiliation	Columbia University, Department of Biochemistry and Molecular Biophysics, USA
contact email	ag4522@cumc.columbia.edu
lab head
Malcolm Wells
contact affiliation	Columbia University NYSBC
contact email	mw3079@columbia.edu
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/2026/01/PXD073482

PRIDE project URI

• PRIDE
  1. PXD073482
     1. Label: PRIDE project
     2. Name: HX-MS study of SHP2, WT and 2 phosphomimic mutants