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

Abstract

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 antiestrogen (tamoxifen)-induced transcriptional activity of wild-type ER, but not that of a mutant ER with an alanine in place of Ser118. Thus, the activity of the amino-terminal AF-1 of the ER is modulated by the phosphorylation of Ser118 through the Ras-MAPK cascade of the growth factor signaling pathways.

Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action

“…Involvement of small GTP-binding proteins, other than Ras (Kato et al, 1995;Bunone et al, 1996), in modulation of ER activity has not been previously reported. It has been suggested that activation of a single GTPase by a Rho-GEF (such as Brx) could trigger a cascade of GTPase activation since GTP-binding proteins exist in tightly linked, but independent, regulatory circuits.…”

“…This raises the possibility that Brx might indirectly a ect Rasdependent activation of the estrogen receptor. However, it does not seem that the growth factor Ras ± Raf ± MAPK pathway of ER activation is a ected by Brx, since activation of ER by the Ras ± Raf ± MAPK pathway was not inhibited by tamoxifen (Kato et al, 1995); whereas, activation of ER by Brx could be abolished by tamoxifen (Figure 5b). It is possible that cell type, or promoter-speci®c di erences might account for the di erences in response to tamoxifen, since we have not observed activation of an estrogenresponsive promter by tamoxifen in Ishikawa cells, as was observed in COS-1 cells (Kato et al, 1995).…”

“…However, it does not seem that the growth factor Ras ± Raf ± MAPK pathway of ER activation is a ected by Brx, since activation of ER by the Ras ± Raf ± MAPK pathway was not inhibited by tamoxifen (Kato et al, 1995); whereas, activation of ER by Brx could be abolished by tamoxifen (Figure 5b). It is possible that cell type, or promoter-speci®c di erences might account for the di erences in response to tamoxifen, since we have not observed activation of an estrogenresponsive promter by tamoxifen in Ishikawa cells, as was observed in COS-1 cells (Kato et al, 1995). Nevertheless, modulation of estrogen action by small GTP-binding proteins may be of clinical signi®cance, since aberrant Ras signal transduction has been associated with oncogenesis, including some estrogenresponsive breast cancers (Clark and Der, 1995).…”

“…Studies have documented e ects upon gene activation by nuclear receptors via epidermal growth factor (EGF) (Kato et al, 1995;Bunone et al, 1996;Ignar-Trowbridge et al, 1993), dopamine (Power et al, 1991;Smith et al, 1993), TGFa, (IgnarTrowbridge et al, 1993), insulin-like-growth factor I (IGF-I) (Aronica and Katzenellenbogen, 1993;, cAMP (Aronica and Katzenellenbogen, 1993;Denner et al, 1990), and heregulin (Pietras et al, 1995). Data from several laboratories suggest that this second pathway of NHR activation may result in either ligand-independent receptor activation (Bunone et al, 1996;Ignar-Trowbridge et al, 1993) or augmentation of ligand-dependent receptor signaling (Aronica and Katzenellenbogen, 1993;Kato et al, 1995;Ingar-Trowbridge et al, 1993). For instance, protein kinases such as protein kinase A (PKA) and protein kinase C (PKC) a ect ligand-dependent activation of ER; an e ect abolished by the addition of the estrogen antagonist, ICI 164384 (Cho and Katzenellenbogen, 1993).…”

“…In vivo studies showed that EGF mimics estrogen regulated functions such as DNA synthesis and augmentation of phosphatidylinositol turnover in the uterus and that both e ects were blocked by the addition of the anti-estrogen, ICI 164384 (Ignar-Trowbridge et al, 1992). Activation of ER by EGF was shown to involve phosphorylation of serine 118 in the amino-terminus of ER through a Ras ± Raf ± mitogen activated protein kinase (MAPK) signaling pathway (Kato et al, 1995;Bunone et al, 1996). Of interest, nuclear translocation of ER could be induced by EGF; an e ect that was inhibited in the presence of a co-transfected dominant negative Ras mutant, rasN17 (Bunone et al, 1996).…”