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Phosphorylation of the hinge domain of the nuclear hormone receptor LRH-1 stimulates transactivation

Cited 64 time in Web of Science Cited 67 time in Scopus
Authors
Lee, Yoon-Kwang; Choi, Yun-Hee; Chua, Steven; Park, Young Joo; Moore, David D
Issue Date
2006-01-28
Publisher
American Society for Biochemistry and Molecular Biology
Citation
J Biol Chem. 2006 Mar 24;281(12):7850-5. Epub 2006 Jan 25.
Keywords
Alanine/chemistryAmino Acid SequenceAnimalsAspartic Acid/chemistryButadienes/pharmacologyCell LineCell Nucleus/*metabolismCholesterol 7-alpha-Hydroxylase/geneticsDNA-Binding Proteins/chemistry/*metabolismExtracellular Signal-Regulated MAP Kinases/metabolismGene Expression RegulationHela CellsHumansLigandsMAP Kinase Signaling SystemMitogensMolecular Sequence DataMutationNitriles/pharmacologyPhosphoproteins/chemistryPhosphorylationPlasmids/metabolismPromoter Regions, GeneticProtein BindingProtein Structure, TertiaryProtein TransportRatsReceptors, Cytoplasmic and Nuclear/*metabolismSequence Homology, Amino AcidSerine/chemistryTetradecanoylphorbol Acetate/chemistryTranscription Factors/chemistry/*metabolismTranscription, GeneticTranscriptional ActivationTransfection
Abstract
The nuclear receptor LRH-1 (NR5A2) functions to regulate expression of a number of genes associated with bile acid homeostasis and other liver functions, but mechanisms that modulate its activity remain unclear. We have found that mitogenic stimuli, including treatment with phorbol myristate (PMA), increase LRH-1 transactivation. This response maps to the hinge and ligand binding domains of LRH-1 and is blocked by the mitogen-activated protein kinase ERK1/2 inhibitor U0126. LRH-1 is a phosphoprotein and hinge domain serine residues at 238 and 243 are required for effective phosphorylation, both in vitro and in cells. Preventing phosphorylation of these residues by mutating both to alanine decreases PMA-dependent LRH-1 transactivation and mimicking phosphorylation by mutation to positively charged aspartate residues increases basal transactivation. Although serine phosphorylation of the hinge of SF-1 (NR5A1), the closest relative of LRH-1, confers a similar response, the specific targets differ in the two closely related orphan receptors. These results define a novel pathway for the modulation of LRH-1 transactivation and identify specific LRH-1 residues as downstream targets of mitogenic stimuli. This pathway may contribute to recently described proliferative functions of LRH-1.
ISSN
0021-9258 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16439367

http://hdl.handle.net/10371/44029
DOI
https://doi.org/10.1074/jbc.M509115200
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College of Medicine/School of Medicine (의과대학/대학원)Molecular and Genomic Medicine (분자유전체의학전공)Journal Papers (저널논문_분자유전체의학전공)
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