Phosphorylation of the nuclear receptor SF-1 modulates cofactor recruitment: integration of hormone signaling in reproduction and stress.
Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor that serves as an essential regulator of many hormone-induced genes in the vertebrate endocrine system. The apparent absence of a SF-1 ligand prompted speculation that this receptor is regulated by alternative mechanisms involving signal transduction pathways. Here we show that maximal SF-1-mediated transcription and interaction with general nuclear receptor cofactors depends on phosphorylation of a single serine residue (Ser-203) located in a major activation domain (AF-1) of the protein. Moreover, phosphorylation-dependent SF-1 activation is likely mediated by the mitogen-activated protein kinase (MAPK) signaling pathway. We propose that this single modification of SF-1 and the subsequent recruitment of nuclear receptor cofactors couple extracellular signals to steroid and peptide hormone synthesis, thereby maintaining dynamic homeostatic responses in stress and reproduction.
Hammer
G D
GD
Department of Physiology, University of California, San Francisco 94143-0444, USA.
Krylova
I
I
Zhang
Y
Y
Darimont
B D
BD
Simpson
K
K
Weigel
N L
NL
Ingraham
H A
HA
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D051717:Fushi Tarazu Transcription Factors; D017930:Genes, Reporter; D018398:Homeodomain Proteins; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D056985:Nuclear Receptor Co-Repressor 2; D051958:Nuclear Receptor Coactivator 2; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D012098:Reproduction; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D054339:Steroidogenic Factor 1; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; C539130:NCOR2 protein, human; C515057:NR5A1 protein, human; D009687:Nuclear Proteins; D056985:Nuclear Receptor Co-Repressor 2; D051958:Nuclear Receptor Coactivator 2; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; D012694:Serine; D004815:Epidermal Growth Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases