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

Abstract

A splicing variant of rat striatin-3 (rSTRN3g) was found to associate with estrogen receptor-a (ERa) in a ligand-dependent manner. In two-hybrid and pull-down analyses, estradiol induced an interaction between rSTRN3g and ERa. STRN3g protein was found in nuclear extracts from rat uterus and human cell lines. Overexpression of rSTRN3g induced a decrease in ERa transcriptional activity but had no effect on ERb activity. Immunoprecipitation analyses showed that rSTRN3g interacts with both the ERa and the catalytic subunit of protein phosphatase 2A (PP2A(C)). The transrepressor action of rSTRN3g was overcome by okadaic acid, an inhibitor of PP2A(C), and by cotransfection of PP2A(C) siRNA. rSTRN3g caused dephosphorylation of ERa at serine 118 and this was abrogated by okadaic acid. ERa lacking phosphorylation sites at either serine 118 or 167 was insensitive to the corepressor action of rSTRN3g. These observations suggest that an rSTRN3g-PP2A(C) complex is recruited to agonist-activated ERa, thereby leading to its dephosphorylation and inhibiting transcription.

Striatins Contain a Noncanonical Coiled Coil That Binds Protein Phosphatase 2A A Subunit to Form a 2:2 Heterotetrameric Core of Striatin-interacting Phosphatase and Kinase (STRIPAK) Complex

“…Striatins are a novel family of Bٞ type regulatory subunits that directly interact with PP2A A subunits, and indirectly interact with some GCKs using adaptor molecules (Fig. 1A) (7)(8)(9)(10)(11)(12). Because inhibition of PP2A using okadaic acid causes phosphorylation of MOB and hyperphosphorylation of striatins, PP2A may thus regulate striatins and the associated MOB proteins to modify the cytoskeleton and its interactions with membrane structures (10,11).…”

“…Localization of striatins to dendritic spines is regulated by cortactin-binding protein 2 (CTTNBP2) (31), which interacts with and regulates the mobility of cortactin to control dendritic spine formation (32). In addition to the aforementioned binding partners, striatins may associate with estrogen receptor ␣ and G␣ i to form a membrane signaling complex that facilitates rapid non-genomic signaling of estrogen receptor ␣ (8,33). Disruption of estrogen receptorstriatin interaction eliminates the ability of estrogen to stimulate cultured endothelial cell migration and to inhibit cultured vascular smooth muscle cell growth (34).…”

Activation of the Mineralocorticoid Receptor Increases Striatin Levels

“…15–17 Striatin contains several protein association domains: a caveolin (cav)-binding motif, a coiled-coil structure, a Ca 2+ -calmodulin-binding site and a large WD-repeat domain. 15,18 There is evidence that striatin’s WD-repeat domain interacts with GαI protein and Protein Phosphatase 2A (PP2A) allowing for rapid activation of several transduction molecules (e.g., endothelial nitric oxide synthase) and mitogen-activated protein kinase 19 …”

STRIPAK complexes: Structure, biological function, and involvement in human diseases

“…The cancer patient serum may recognize an SG2NA epitope only accessible in immunofluorescence staining on a nuclear-localized splice variant of SG2NA. Consistent with this possibility, rSTRN3γ, a novel, nuclear-localized splice variant of rat SG2NA lacking all but one WD-repeat was recently reported to organize an estrogen-inducible complex of PP2A and estrogen receptor α (ERα) (Tan et al, 2008). Also consistent with possible nuclear function, the N-terminal region of SG2NA has been reported to possess transcriptional activation activity, although this activity was largely absent in the context of the full-length protein (Zhu et al, 2001).…”

“…In our discussions below, we will make this distinction in terminology, realizing that in some cases the association of PP2A or a kinase may occur and may simply not have been demonstrated yet. Examples of STRIPAK-like complexes include both nuclear (Tan et al, 2008) and plasma membrane (Lu et al, 2004) striatin family complexes that regulate genomic and non-genomic estrogen signaling, respectively. These will be discussed below in section 4.2.…”