Striatin-3γ inhibits estrogen receptor activity by recruiting a protein phosphatase

A splicing variant of rat striatin-3 (rSTRN3 gamma) was found to associate with estrogen receptor-alpha (ER alpha) in a ligand-dependent manner. In two-hybrid and pull-down analyses, estradiol induced an interaction between rSTRN3 gamma and ER alpha. STRN3 gamma protein was found in nuclear extracts from rat uterus and human cell lines. Overexpression of rSTRN3 gamma induced a decrease in ERa transcriptional activity but had no effect on ER beta activity. Immunoprecipitation analyses showed that rSTRN3 gamma interacts with both the ER alpha. and the catalytic subunit of protein phosphatase 2A (PP2A(C)). The transrepressor action of rSTRN3 gamma was overcome by okadaic acid, an inhibitor of PP2A(C), and by cotransfection of PP2A(C) siRNA. rSTRN3 gamma caused dephosphorylation of ER alpha at serine 118 and this was abrogated by okadaic acid. ER alpha, lacking phosphorylation sites at either serine 118 or 167 was insensitive to the corepressor action of rSTRN3 gamma. These observations suggest that an rSTRN3 gamma-PP2A(C) complex is recruited to agonist-activated ER alpha, thereby leading to its dephosphorylation and inhibiting transcription.