Phosphorylation of the hinge domain of the nuclear hormone receptor LRH-1 stimulates transactivation.
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.
Lee
Yoon-Kwang
YK
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ylee@bcm.tmc.edu
Choi
Yun-Hee
YH
Chua
Steven
S
Park
Young Joo
YJ
Moore
David D
DD
D000409:Alanine / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System; D008934:Mitogens; D008969:Molecular Sequence Data; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D010750:Phosphoproteins / Q000737:chemistry; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D000072260:RNA Splicing Factors; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000737:chemistry; D013755:Tetradecanoylphorbol Acetate / Q000737:chemistry; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D002070:Butadienes; D004268:DNA-Binding Proteins; D008024:Ligands; D008934:Mitogens; C082631:NR5A2 protein, human; D009570:Nitriles; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D018160:Receptors, Cytoplasmic and Nuclear; C107467:SF1 protein, human; D014157:Transcription Factors; C113580:U 0126; D001224:Aspartic Acid; D012694:Serine; D002790:Cholesterol 7-alpha-Hydroxylase; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate; D000409:Alanine