PXD041563

PXD041563 is an original dataset announced via ProteomeXchange.

Title	Increased Basal MET phosphorylation is a Hallmark of Hepatocyte Dysregulation in Liver Disease: Mouse
Description	Non-alcoholic fatty liver disease (NAFLD) is gaining evermore importance due to rapidly rising incidence rates especially in western countries. As the disease progresses, it can develop into hepatocellular carcinoma. Related metabolic changes have been extensively studied in the past. However, the molecular mechanisms responsible for the development of fatty liver disease remain uncovered. Here we show that the basal phosphorylation of the MET receptor can be used as an indicator for hepatocyte dysregulation in fatty liver disease. Using primary hepatocytes isolated from a preclinical model fed with high-fat, high-sugar diet (Western diet; WD) or standard diet (SD), we find a strong downregulation of the PI3K-AKT pathway and upregulation of the MAPK pathway in the WD derived hepatocytes. By developing a mathematical model of HGF-induced signal transduction, calibrated with quantitative time-resolved measurements of both PI3K-AKT and MAPK pathways, we resolve molecular mechanisms responsible for these alterations. Thereby, we identify the basal MET phosphorylation rate as main driver for the altered signal transduction in WD hepatocytes that even leads to an increased proliferation behavior of the usually quiescent hepatocytes in the absence of growth factors. The adaptation of the dynamic pathway model of HGF signal transduction to patient-derived hepatocytes reveals a patient-specific variability of basal MET phosphorylation levels, which correlates with the clinical outcome of patients after liver surgery. These findings suggest that the dysregulated basal MET phosphorylation could be exploited to assess the health status of the liver and thereby inform estimation of the risk of a patient to suffer from liver failure after surgery.
HostingRepository	PRIDE
AnnounceDate	2024-01-15
AnnouncementXML	Submission_2024-01-15_00:40:56.427.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marcel Schilling
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-16 14:34:46	ID requested
⏵ 1	2024-01-15 00:40:57	announced

Burbano de Lara S, Kemmer S, Biermayer I, Feiler S, Vlasov A, D'Alessandro LA, Helm B, M, ö, lders C, Dieter Y, Ghallab A, Hengstler JG, K, ö, rner C, Matz-Soja M, G, ö, tz C, Damm G, Hoffmann K, Seehofer D, Berg T, Schilling M, Timmer J, Klingm, ü, ller U, Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease. Mol Syst Biol, 20(3):187-216(2024) [pubmed]

10.1038/s44320-023-00007-4;

submitter keyword: Western diet

dynamic pathway modeling

hepatocyte dysregulation

fatty liver disease

HGF signal transduction

Ursula Klingmüller
contact affiliation	Division Systems Biology of Signal Transduction German Cancer Research Center (DKFZ)
contact email	u.klingmueller@dkfz.de
lab head
Marcel Schilling
contact affiliation	Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg
contact email	m.schilling@dkfz.de
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/2024/01/PXD041563

PRIDE project URI

• PRIDE
  1. PXD041563
     1. Label: PRIDE project
     2. Name: Increased Basal MET phosphorylation is a Hallmark of Hepatocyte Dysregulation in Liver Disease: Mouse