SPBP is a phosphoserine-specific repressor of estrogen receptor α

Multiple signaling pathways stimulate the activity of estrogen receptor alpha (ER alpha) 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 ER alpha 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 ER alpha. Functionally, SPBP behaved as a repressor of activated ER alpha, 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 ERa activity. A functional consequence is that SPBP inhibits the proliferation of ER alpha-dependent but not ER alpha-independent breast cancer cell lines, mirroring a reported negative correlation with the ER alpha status of breast tumors.