PXD058196

PXD058196 is an original dataset announced via ProteomeXchange.

Title	Erk1R84H is an oncoprotein that causes hepatocellular carcinoma in mice and imposes rigorous negative feedback loop on the RTK-Ras-Raf-MEK pathway- Global proteomics
Description	The extracellular signal-regulated kinases (Erks), Erk1 and Erk2, are crucial components of the receptor tyrosine kinase (RTK)-Ras-Raf-MEK pathway, which is frequently mutated and constitutively activated in various cancers. Despite Erk activity being commonly observed in cancer, the role of direct Erk activation in driving tumorigenesis remains unproven. This study explores the oncogenic potential of intrinsically active Erk1 mutants, particularly Erk1R84H, in both in vivo and in vitro models. We established a transgenic mouse model enabling tissue-specific and temporally controlled expression of Erk1R84H. Upon inducing Erk1R84H expression in the liver, we observed the development of hepatocellular carcinoma (HCC) characterized by increased liver weight, necrosis, and significant loss of body weight. Intriguingly, the phosphorylated/active form of Erk1R84H was dramatically downregulated during HCC development, becoming almost undetectable in mature tumors. This phenomenon was mirrored in NIH3T3 cells transformed by Erk1R84H, where TEY phosphorylation was significantly reduced as transformed foci appeared. Our proteomic and phosphoproteomic analyses of stable clones expressing Erk1R84H or Erk1R84S revealed substantial changes in protein expression and kinase activity. Key findings included the upregulation of CDK1, AURKB, and CDK2, and the downregulation of DNA repair and circadian rhythm-related kinases. Notably, Upp1, a crucial enzyme in nucleotide metabolism, was highly upregulated in clones transformed by Erk1R84S or Erk1R84H, suggesting its role in supporting the transformed phenotype. Furthermore, we demonstrated that the feedback inhibition mechanism suppressing Erk phosphorylation is dependent on Erk activity itself. Inhibition of Erk1R84H or Erk1R84S with Erk inhibitors restored TEY phosphorylation, highlighting the importance of precise rather very low Erk activity in maintaining the transformed state. In summary, Erk1R84H is confirmed as an efficient oncoprotein capable of inducing HCC in vivo and transforming cells in culture. The mechanism it uses for transformation, involving significant down regulation of its own activity underscores the notion that too high oncogenic activity is not favored by the tumor and proposes a modified therapeutic approach of targeting Erk for its activation rather than inhibition.
HostingRepository	PRIDE
AnnounceDate	2025-08-04
AnnouncementXML	Submission_2025-08-03_16:38:53.348.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: 10090;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-24 10:50:51	ID requested
⏵ 1	2025-08-03 16:38:54	announced

Soudah N, Baskin A, Darash-Yahana M, Darlyuk-Saadon I, Smorodinsky-Atias K, Shalit T, Yu WP, Savidor A, Pikarsky E, Engelberg D, is an oncoprotein that causes hepatocellular carcinoma in mice and imposes a rigorous negative feedback loop. Oncogene, 44(31):2689-2714(2025) [pubmed]

10.1038/s41388-025-03437-6;

submitter keyword: proteomics, phosphorylation, MAPK, phosphoproteomics, Kinase, autoactivation,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. PXD058196
     1. Label: PRIDE project
     2. Name: Erk1R84H is an oncoprotein that causes hepatocellular carcinoma in mice and imposes rigorous negative feedback loop on the RTK-Ras-Raf-MEK pathway- Global proteomics