Activation of the Estrogen Receptor Through Phosphorylation by Mitogen-Activated Protein Kinase

  title={Activation of the Estrogen Receptor Through Phosphorylation by Mitogen-Activated Protein Kinase},
  author={Shigeaki Kato and Hideki Endoh and Yoshikazu Masuhiro and Takuya Kitamoto and Shimami Uchiyama and Haruna Sasaki and Shoichi Masushige and Yukiko Gotoh and Eisuke Nishida and Hiroyuki Kawashima and Daniel Metzger and Pierre Chambon},
  pages={1491 - 1494}
The phosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for full activity of the ER activation function 1 (AF-1). This Ser118 is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro and in cells treated with epidermal growth factor (EGF) and insulin-like growth factor (IGF) in vivo. Overexpression of MAPK kinase (MAPKK) or of the guanine nucleotide binding protein Ras, both of which activate MAPK, enhanced estrogen-induced and… 

Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation.

It is shown that EGF activates the ER by signaling through the MAPK pathway suggesting that MAPK directly phosphorylates the critical serine 118, and implies that the steroid‐independent activation of a variety of ER mutants, which arise during the malignant progression of breast tumors, may contribute to tamoxifen resistance.

Estradiol-induced Phosphorylation of Serine 118 in the Estrogen Receptor Is Independent of p42/p44 Mitogen-activated Protein Kinase*

The data suggest that a kinase other than p42/p44 MAPK is involved in the estradiol-induced Ser118phosphorylation, and it is proposed that the hormone-induced change in ER conformation exposes Ser118 for phosphorylation by a constitutively active kinase.

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

It is shown that ERα is phosphorylated by protein kinase A (PKA) on serine-236 within the DNA binding domain and 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 ligandbinding.

Phosphorylation of human estrogen receptor α at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-specific antisera

It is shown that MAPK phosphorylates S118 in a ligand-independent manner, whereas Cdk7 mediates E2-induced phosphorylation of S118, and that ERα is phosphorylated at S 118 in vivo using immunoblotting of extracts prepared from a series of ERα-positive breast tumours.

Regulation of Estrogen Receptor-Dependent Transcriptional Activation by a Cyclin-Dependent Kinase.

Abstract : The estrogen receptor a is transcription factor that is regulated by ligand binding and phosphorylation. The phosphorylation of three serine residues (S104, S106 and S118) located within

Rapid activation of MAP kinase by estrogen in the bone cell line.

The data provide the first evidence of MAPK activation by E2 through phosphorylation, which may be mediated through a putative plasma membrane receptor in the cultured bone cells.

Phosphorylation at serines 104 and 106 by Erk1/2 MAPK is important for estrogen receptor-α activity

Data indicate that the MAPK stimulation of ERα activity involves the phosphorylation not only of S118 but also of S104 and S106, and that MAPK-mediated hyperphosphorylation of ER α at these sites may contribute to resistance to tamoxifen in breast cancer.

Phosphatidylinositol 3-Kinase/AKT-mediated Activation of Estrogen Receptor α

A molecular link between activation of the PI 3-kinase/AKT survival pathways, hormone-independent activation of ERα, and inhibition of tamoxifen-induced apoptotic regression is defined.



Peptide growth factors elicit estrogen receptor-dependent transcriptional activation of an estrogen-responsive element.

In vivo observations indicate that EGF may elicit some of its actions by activation of the ER, and the presence of cross-talk between EGF receptor and ER signaling pathways suggests that interactions between growth factors and steroid receptors may modulate hormonal activity influencing normal and aberrant function in mammalian cells.

Stimulation of estrogen receptor-mediated transcription and alteration in the phosphorylation state of the rat uterine estrogen receptor by estrogen, cyclic adenosine monophosphate, and insulin-like growth factor-I.

The results of this study indicate that E2, IGF-I, and agents which raise intracellular cAMP are able to stimulate ER-mediated trans-activation and ER phosphorylation.

Modulation of transcriptional activation by ligand‐dependent phosphorylation of the human oestrogen receptor A/B region.

Using a transient co‐transfection system, we show that the human oestrogen receptor (hER) becomes phosphorylated in the presence of oestradiol (E2) as well as in the presence of the anti‐oestrogens

Characterization of the Amino-terminal Transcriptional Activation Function of the Human Estrogen Receptor in Animal and Yeast Cells (*)

It is shown that in animal cells the “independent” activity of AF-1 is embodied in a rather hydrophobic proline-rich 99-amino acid activating domain (amino acids 51-149), whereas in yeast, three discrete activating domains are almost as active on their own as the whole A/B region, indicating that multiple activating domains can operate independently in yeast.