Phospho-ESR1 (Ser167)

This gene encodes an estrogen receptor, a ligand-activated transcription factor composed of several domains important for hormone binding, DNA binding, and activation of transcription. The protein localizes to the nucleus where it may form a homodimer or a heterodimer with estrogen receptor 2. Estrogen and its receptors are essential for sexual development and reproductive function, but also play a role in other tissues such as bone. Estrogen receptors are also involved in pathological processes including breast cancer, endometrial cancer, and osteoporosis. Alternative promoter usage and alternative splicing result in dozens of transcript variants, but the full-length nature of many of these variants has not been determined. [provided by RefSeq, Mar 2014]

Estrogen Receptor 1

Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3 (PubMed:17922032).

Isoform 3:
Involved in activation of NOS3 and endothelial nitric oxide production (PubMed:21937726).

Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full-length receptor (PubMed:10970861).

Binds to ERE and inhibits isoform 1 (PubMed:10970861).

Androgen metabolic process Source: Ensembl
Antral ovarian follicle growth Source: Ensembl
Cellular response to estradiol stimulus Source: ARUK-UCL
Cellular response to estrogen stimulus Source: Ensembl
Chromatin remodeling Source: UniProtKB
Epithelial cell development Source: Ensembl
Epithelial cell proliferation involved in mammary gland duct elongation Source: Ensembl
Intracellular estrogen receptor signaling pathway Source: CAFA
Intracellular steroid hormone receptor signaling pathway Source: UniProtKB
Male gonad development Source: Ensembl
Mammary gland alveolus development Source: Ensembl
Mammary gland branching involved in pregnancy Source: Ensembl
Negative regulation of DNA-binding transcription factor activity Source: UniProtKB
Negative regulation of gene expression Source: UniProtKB
Negative regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
Negative regulation of production of miRNAs involved in gene silencing by miRNA Source: BHF-UCL
Negative regulation of transcription by RNA polymerase II Source: BHF-UCL
Phospholipase C-activating G protein-coupled receptor signaling pathway Source: UniProtKB
Positive regulation of cytosolic calcium ion concentration Source: UniProtKB
Positive regulation of DNA-binding transcription factor activity Source: UniProtKB
Positive regulation of fibroblast proliferation Source: Ensembl
Positive regulation of nitric oxide biosynthetic process Source: UniProtKB
Positive regulation of nitric-oxide synthase activity Source: UniProtKB
Positive regulation of phospholipase C activity Source: UniProtKB
Positive regulation of RNA polymerase II transcription preinitiation complex assembly Source: CAFA
Positive regulation of transcription, DNA-templated Source: UniProtKB
Positive regulation of transcription by RNA polymerase II Source: UniProtKB
Prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis Source: Ensembl
Prostate epithelial cord elongation Source: Ensembl
Protein localization to chromatin Source: BHF-UCL
Regulation of apoptotic process Source: Ensembl
Regulation of branching involved in prostate gland morphogenesis Source: Ensembl
Regulation of inflammatory response Source: Ensembl
Regulation of toll-like receptor signaling pathway Source: Ensembl
Regulation of transcription, DNA-templated Source: UniProtKB
Regulation of transcription by RNA polymerase II Source: GO_Central
Response to estradiol Source: BHF-UCL
Response to estrogen Source: UniProtKB
Signal transduction Source: ProtInc
Stem cell differentiation Source: Ensembl
Uterus development Source: Ensembl
Vagina development Source: Ensembl

Isoform 1: Cell membrane; Nucleus; Cytoplasm. A minor fraction is associated with the inner membrane.
Isoform 3: Cell membrane; Nucleus; Cytoplasm. Associated with the inner membrane via palmitoylation (Probable). At least a subset exists as a transmembrane protein with a N-terminal extracellular domain.
Cell membrane; Golgi apparatus; Nucleus. Colocalizes with ZDHHC7 and ZDHHC21 in the Golgi apparatus where most probably palmitoylation occurs. Associated with the plasma membrane when palmitoylated.

Estrogen resistance (ESTRR):
A disorder characterized by partial or complete resistance to estrogens, in the presence of elevated estrogen serum levels. Clinical features include absence of the pubertal growth spurt, delayed bone maturation, unfused epiphyses, reduced bone mineral density, osteoporosis, continued growth into adulthood and very tall adult stature. Glucose intolerance, hyperinsulinemia and lipid abnormalities may also be present.

Phosphorylated by cyclin A/CDK2 and CK1. Phosphorylation probably enhances transcriptional activity. Self-association induces phosphorylation. Dephosphorylation at Ser-118 by PPP5C inhibits its transactivation activity. Phosphorylated by LMTK3 in vitro.
Glycosylated; contains N-acetylglucosamine, probably O-linked.
Ubiquitinated; regulated by LATS1 via DCAF1 it leads to ESR1 proteasomal degradation (PubMed:21602804, PubMed:28068668). Deubiquitinated by OTUB1 (PubMed:19383985).
Dimethylated by PRMT1 at Arg-260. The methylation may favor cytoplasmic localization (PubMed:18657504, PubMed:24498420). Demethylated by JMJD6 at Arg-260 (PubMed:24498420).
Palmitoylated (isoform 3). Not biotinylated (isoform 3).
Palmitoylated by ZDHHC7 and ZDHHC21. Palmitoylation is required for plasma membrane targeting and for rapid intracellular signaling via ERK and AKT kinases and cAMP generation, but not for signaling mediated by the nuclear hormone receptor.