PXD069633

PXD069633 is an original dataset announced via ProteomeXchange.

Title	Similar effects of various Erk inhibitors: interception of negative feedback, activation of p38, imposing cell cycle arrest, and maintaining cell viability
Description	The MAP kinases Erk1/2 are the major mediators of the oncogenicity of the Receptor tyrosine kinase (RTK)-Ras-Raf-MEK cascade. As components of this pathway are often mutated and constantly active in cancer, Erks are regarded as promising targets for therapy for many types of malignancies. Yet, while active Erks are promoting abnormal cell proliferation, they simultaneously also inhibit upstream components of the pathway. Erks’ inhibition causes, therefore, reactivation of proto-oncogenic proteins hence Erks’ inhibitors must be applied causiously. Here we studied the effects of Erks’ inhibitors on cells transformed by oncogenic variants of Erk1, Erk1R84H and Erk1R84S, in which the negative feedback effect is so powerful that Erks’ phosphorylation could not be monitored. We show that provision of either BVD523, SCH772984, ASN007, Temuterkib or GCD0994, led to re-appearance of high phosphorylation levels of Erks, suggesting that all inhibitors intercepted Erks-mediated negative feedback activity. We found that inhibitors-mediated Erks’ re-phosphorylation is dependent entirely on MEK activation and that the highly phosphorylated Erk molecules are catalytically inactive. All inhibitors caused cell cycle arrest at the G1 phase, by inducing elevation of p21Cip1/Waf1 and Klf4, but did not affect cell viability for at least 72 hours. They also caused activation of the MAP/stress kinase p38. Proteome and phosphoproteome analysis of BVD523-treated cells revealed effect of the drug on the Rho GTPase pathway and on MAPK targets. The 5 inhibitors were further tested on a battery of 9 cancer-derived cell lines and in many of them most of the effects were similar to those observed with the Erk1R84H- and Erk1R84S-transformed NIH3T3 cells
HostingRepository	PRIDE
AnnounceDate	2026-05-18
AnnouncementXML	Submission_2026-05-18_06:48:29.893.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alon Savidor
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	phosphorylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF; Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-19 09:14:57	ID requested
⏵ 1	2026-05-18 06:48:30	announced

Dataset with its publication pending

submitter keyword: BVD523 (Ulixertinib), MAP kinase, ASN007, p38, Temuterkib (LY3214996), cis-platin, MEK, phosphoproteomics, SCH772984, GCD0994 (Ravoxertinib),Erk

Prof. David Engelberg
contact affiliation	Dept. of Biological Chemistry The Institute of Life Science The Hebrew University of Jerusalem Jerusalem 91904, Israel
contact email	engelber@mail.huji.ac.il
lab head
Alon Savidor
contact affiliation	The Weizmann Institute of Science
contact email	alon.savidor@weizmann.ac.il
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD069633
     1. Label: PRIDE project
     2. Name: Similar effects of various Erk inhibitors: interception of negative feedback, activation of p38, imposing cell cycle arrest, and maintaining cell viability