SPBP is a phosphoserine-specific repressor of estrogen receptor alpha.
Multiple signaling pathways stimulate the activity of estrogen receptor alpha (ERalpha) by direct phosphorylation within its N-terminal activation function 1 (AF1). How phosphorylation affects AF1 activity remains poorly understood. We performed a phage display screen for human proteins that are exclusively recruited to the phosphorylated form of AF1 and found the stromelysin-1 platelet-derived growth factor-responsive element-binding protein (SPBP). In a purified system, SPBP bound only the in vitro-phosphorylated form of the ERalpha AF1 or the phosphoserine mimic S118E, and the interaction domain could be mapped to a 42-amino-acid fragment of SPBP. In cells, SPBP preferentially interacted with liganded and phosphorylated ERalpha. Functionally, SPBP behaved as a repressor of activated ERalpha, which extends its previously demonstrated roles as a DNA binding transactivation factor and coactivator of other transcription factors. By targeting the phosphorylated form of AF1, SPBP may contribute to attenuating and fine-tuning ERalpha activity. A functional consequence is that SPBP inhibits the proliferation of ERalpha-dependent but not ERalpha-independent breast cancer cell lines, mirroring a reported negative correlation with the ERalpha status of breast tumors.
Gburcik
Valentina
V
Department of Cell Biology, Sciences III, University of Geneva, 30 quai Ernest-Ansermet, 1211 Geneva 4, Switzerland.
Bot
Nathalie
N
Maggiolini
Marcello
M
Picard
Didier
D
D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D019151:Peptide Library; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D047628:Estrogen Receptor alpha; D019151:Peptide Library; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C114750:TCF20 protein, human; D014157:Transcription Factors; D010768:Phosphoserine