scholarly journals Rapid Estrogen-Induced Phosphorylation of the SRC-3 Coactivator Occurs in an Extranuclear Complex Containing Estrogen Receptor

2005 ◽  
Vol 25 (18) ◽  
pp. 8273-8284 ◽  
Author(s):  
Fuzhong F. Zheng ◽  
Ray-Chang Wu ◽  
Carolyn L. Smith ◽  
Bert W. O'Malley
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Direct Interaction ◽  
Activation Function ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Phosphorylation Sites ◽  
Binding Domains ◽  
Nongenomic Action ◽  
Binding Groove

ABSTRACT SRC-3/AIB1/ACTR/pCIP/RAC3/TRAM1 is a primary transcriptional coregulator for estrogen receptor (ER). Six SRC-3 phosphorylation sites have been identified, and these can be induced by steroids, cytokines, and growth factors, involving multiple kinase signaling pathways. Using phosphospecific antibodies for six phosphorylation sites, we investigated the mechanisms involved in estradiol (E2)-induced SRC-3 phosphorylation and found that this occurs only when either activated estrogen receptor α (ERα) or activated ERβ is present. Both the activation function 1 and the ligand binding domains of ERα are required for maximal induction. Mutations in the coactivator binding groove of the ERα ligand binding domain inhibit E2-stimulated SRC-3 phosphorylation, as do mutations in the nuclear receptor-interacting domain of SRC-3, suggesting that ERα must directly contact SRC-3 for this posttranslational modification to take place. A transcriptionally inactive ERα mutant which localizes to the cytoplasm supports E2-induced SRC-3 phosphorylation. Mutations of the ERα DNA binding domain did not block this rapid E2-dependent SRC-3 phosphorylation. Together these data demonstrate that E2-induced SRC-3 phosphorylation is dependent on a direct interaction between SRC-3 and ERα and can occur outside of the nucleus. Our results provide evidence for an early nongenomic action of ER on SRC-3 that supports the well-established downstream genomic roles of estrogen and coactivators.

scholarly journals Correction to: Targeted degradation of activating estrogen receptor α ligand-binding domain mutations in human breast cancer

2020 ◽  
Vol 180 (3) ◽  
pp. 623-623
Author(s):  
Thomas L. Gonzalez ◽  
Molly Hancock ◽  
Siqi Sun ◽  
Christina L. Gersch ◽  
Jose M. Larios ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Ligand Binding ◽  
Human Breast Cancer ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Human Breast

Monitoring ligand-mediated helix 12 transitions within the human estrogen receptor α using bipartite tetracysteine display

2020 ◽  
Vol 18 (31) ◽  
pp. 6063-6071
Author(s):  
Ranju Pokhrel ◽  
Tang Tang ◽  
Justin M. Holub
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Estrogen Receptor Α ◽  
Fluorescent Labeling ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Human Estrogen Receptor ◽  
Helix 12

Fluorescent labeling coupled with bipartite tetracysteine display enables the surveillance of ligand-mediated helix 12 transitions within the estrogen receptor α ligand-binding domain.

scholarly journals Identification of Regions within the F Domain of the Human Estrogen Receptor α that Are Important for Modulating Transactivation and Protein-Protein Interactions

2007 ◽  
Vol 21 (4) ◽  
pp. 829-842 ◽  
Author(s):  
Akiko Koide ◽  
Changqing Zhao ◽  
Misuzu Naganuma ◽  
Judith Abrams ◽  
Sarah Deighton-Collins ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Protein Interactions ◽  
Mammalian Cells ◽  
Steroid Receptor ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Steroid Receptor Coactivator ◽  
Human Estrogen Receptor

Abstract The estrogen receptor (ER)α is a biologically and clinically important ligand-modulated transcription factor. The F domain of the ERα modulates its functions in a ligand-, promoter-, and cell-specific manner. To identify the region(s) responsible for these functions, we characterized the effects of serial truncations within the F domain. We found that truncating the last 16 residues of the F domain altered the activity of the human ERα (hERα) on an estrogen response element-driven promoter in response to estradiol or 4-hydroxytamoxifen (4-OHT), its sensitivity to overexpression of the coactivator steroid receptor coactivator-1 in mammalian cells, and its interaction with a receptor-interacting domain of the coactivator steroid receptor coactivator-1 or engineered proteins (“monobodies”) that specifically bind to ERα/ligand complexes in a yeast two-hybrid system. Most importantly, the ability of the ER to induce pS2 was reduced in MDA-MB-231 cells stably expressing this truncated ER vs. the wild-type ER. The region includes a distinctive segment (residues 579–584; LQKYYIT) having a high content of bulky and/or hydrophobic amino acids that was previously predicted to adopt a β-strand-like structure. As previously reported, removal of the entire F domain was necessary to eliminate the agonist activity of 4-OHT. In addition, mutation of the vicinal glycine residues between the ligand-binding domain and F domains specifically reduced the 4-OHT-dependent interactions of the hERα ligand-binding domain and F domains with monobodies. These results show that regions within the F domain of the hERα selectively modulate its activity and its interactions with other proteins.

scholarly journals Phosphorylation of Human Estrogen Receptor α by Protein Kinase A Regulates Dimerization

1999 ◽  
Vol 19 (2) ◽  
pp. 1002-1015 ◽  
Author(s):  
Dongsheng Chen ◽  
Paul E. Pace ◽  
R. Charles Coombes ◽  
Simak Ali
Keyword(s):  
Estrogen Receptor ◽  
Protein Kinase ◽  
Dna Binding ◽  
Ligand Binding ◽  
Protein Kinase A ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Ici 182,780 ◽  
Kinase A

ABSTRACT Phosphorylation provides an important mechanism by which transcription factor activity is regulated. Estrogen receptor α (ERα) is phosphorylated on multiple sites, and stimulation of a number of growth factor receptors and/or protein kinases leads to ligand-independent and/or synergistic increase in transcriptional activation by ERα in the presence of estrogen. Here we show that ERα is phosphorylated by protein kinase A (PKA) on serine-236 within the DNA binding domain. Mutation of serine-236 to glutamic acid prevents DNA binding by inhibiting dimerization by ERα, whereas mutation to alanine has little effect on DNA binding or dimerization. Furthermore, PKA overexpression or activation of endogenous PKA inhibits dimerization in the absence of ligand. This inhibition is overcome by the addition of 17β-estradiol or the partial agonist 4-hydroxy tamoxifen. Interestingly, treatment with the complete antagonist ICI 182,780 does not overcome the inhibitory effect of PKA activation. Our results indicate that in the absence of ligand ERα forms dimers through interaction between DNA binding domains and that dimerization mediated by the ligand binding domain only occurs upon ligand binding but that the complete antagonist ICI 182,780 prevents dimerization through the ligand-binding domain. Heterodimer formation between ERα and ERβ is similarly affected by PKA phosphorylation of serine 236 of ERα. However, 4-hydroxytamoxifen is unable to overcome inhibition of dimerization by PKA. Thus, phosphorylation of ERα in the DNA binding domain provides a mechanism by which dimerization and thereby DNA binding by the estrogen receptor is regulated.

Targeted degradation of activating estrogen receptor α ligand-binding domain mutations in human breast cancer

2020 ◽  
Vol 180 (3) ◽  
pp. 611-622 ◽  
Author(s):  
Thomas L. Gonzalez ◽  
Molly Hancock ◽  
Siqi Sun ◽  
Christina L. Gersch ◽  
Jose M. Larios ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Ligand Binding ◽  
Human Breast Cancer ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Human Breast
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