PXD034183

PXD034183 is an original dataset announced via ProteomeXchange.

Title	Phosphorylation of RXRa mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome
Description	The cJun NH2-terminal kinase (JNK) signaling pathway in the liver promotes systemic changes in metabolism by regulating PPARa-dependent expression of the hepatokine FGF21. Hepatocyte-specific gene ablation studies demonstrated that the Mapk9 gene (encodes JNK2) plays a key mechanistic role. Mutually exclusive inclusion of exons 7a and 7b yields expression of the isoforms JNK2a and JNK2b. Here we demonstrate that Fgf21 gene expression and metabolic regulation is primarily regulated by the JNK2a isoform. To identify relevant substrates of JNK2a, we performed a quantitative phosphoproteomic study of livers isolated from control mice, mice with JNK-deficiency in hepatocytes, and mice that express only JNK2a or JNK2b in hepatocytes. We identified the JNK substrate RXRa as a protein that exhibited JNK2a-promoted phosphorylation in vivo. RXRa functions as a heterodimeric partner of PPARa and may therefore mediate the effects of JNK2a signaling on Fgf21 expression. To test this hypothesis, we established mice with hepatocyte-specific expression of wild-type or mutated RXRa proteins. We found that the RXRa phosphorylation site Ser260 was required for suppression of Fgf21 gene expression. Collectively, these data establish a JNK-mediated signaling pathway that regulates hepatic Fgf21 expression.
HostingRepository	PRIDE
AnnounceDate	2022-10-12
AnnouncementXML	Submission_2022-10-12_08:11:00.897.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	MartaIsasa
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-05-29 13:51:28	ID requested
⏵ 1	2022-10-12 08:11:01	announced

Dataset with its publication pending

submitter keyword: metabolism, FGF21, RXR,JNK, liver, phosphorylation

Roger J.Davis
contact affiliation	Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
contact email	Roger.Davis@umassmed.edu
lab head
MartaIsasa
contact affiliation	Odyssey Therapeutics
contact email	isasa.marta@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD034183
     1. Label: PRIDE project
     2. Name: Phosphorylation of RXRa mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome