Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor.

Joel, Peteranne B.; Traish, Abdulmaged M.; Lannigan, Deborah A.

doi:10.1210/mend.9.8.7476978

Cited by 69 publications

(82 citation statements)

References 16 publications

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“…This may be interpreted as a ligandindependent phosphorylation/activation of ERa. Our data are in line with results from Le Goff et al (1994) and Joel et al (1995), who showed that TPA caused phosphorylation of Ser118 of the human ER expressed in Cos-1 cells. However, TPA-induced ERa phosphorylation was not due to PKCd as it was not inhibited by RDd expression or Rottlerin treatment.…”

Section: Discussionsupporting

confidence: 93%

Impact of PKCδ on estrogen receptor localization and activity in breast cancer cells

et al. 2005

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Regulation of estrogen receptor (ER) function in breast cancer cells is a complex process involving different signalling mechanisms. One signal transduction component that appears to influence ER signalling is protein kinase C (PKC). PKCd is a particular isoenzyme of the novel PKC subfamily that plays a role in growth control, differentiation and apoptosis. The aim of the present study was to investigate the impact of PKCd on the regulation of the transcriptional activity of the human ERa. By using 12-O-tetradecanoylphorbol-13-acetate (TPA), Bryostatin1 and Rottlerin, we show that active PKCd is a proproliferative factor in estrogen-dependent breast cancer cells. Furthermore, activation of PKCd by TPA resulted in activation and nuclear translocation of ERa and in an increase of ER-dependent reporter gene expression. Transfection and expression of the regulatory domain RDd of PKCd, which is inhibitory to PKCd, inhibited the TPA-induced ERa activation and translocation. ERa was not phosphorylated by PKCd; however, glycogen synthase kinase-3 (GSK3) was identified as a substrate of PKCd. The expression of RDd resulted in a decrease of TPA-induced GSK3 phosphorylation and translocation into the nucleus. We suggest that GSK3 plays a role in the PKCd-related nuclear translocation of ERa.

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Section: Discussionsupporting

confidence: 93%

Impact of PKCδ on estrogen receptor localization and activity in breast cancer cells

et al. 2005

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“…The human ERa AF-1 is potentiated by the phosphorylation of the Ser 118 residue of human ERa A/B domain In 1993, three independent groups showed that E2 binding induces phosphorylation of the Ser 118 residue of human ERa (Ali et al 1993;Arnold et al 1995;Joel et al 1995), and furthermore, one of them demonstrated that this phosphorylation potentiates the AF-1 function (Ali et al 1993). We therefore searched for a kinase that was responsible for this phosphorylation of Ser 118 in hERa, and consequently found that the amino acid sequences around Ser 118 in hERa are well conserved over many species, and match a consensus phosphorylation site (PXXSP) recognized by MAP kinase (MAPK) (Gonzalez et al 1991).…”

Section: Molecular Mechanism Of the Novel Cross-talk Between Oestrogementioning

confidence: 99%

Molecular mechanism of a cross‐talk between oestrogen and growth factor signalling pathways

et al. 2000

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Oestrogen (E 2 ) plays signi®cant roles in variety of biological events such as the development and maintenance of female reproductive organs, bone and lipid metabolisms. More recently, from study of knock-out mice de®cient in oestrogen receptor (ER) a and ERb it turned out that normal spermatogenesis requires the E 2 actions. Furthermore, this female steroid hormone is also well known to be deeply involved in many pathophysiological events such as osteoporosis and cancer development in female reproductive organs. It is particularly well known that most breast cancer is dependent on E 2 in its development. Such E 2 actions are thought to be mediated through two subtypes of ERs. Growth factors have been shown to synergize in this E 2 signalling pathway, although the actual molecular mechanism largely remains unknown.Recently, we found that the MAP kinase activated by growth factors phosphorylates the Ser 118 residue of the human ERa A/B domain and this phosphorylation potentiates the N-terminal transactivation function (AF-1) of human ERa, indicating the possible molecular mechanism of a novel cross-talk between E 2 and growth factor signalling pathways. More recently, we have identi®ed a coactivator associating with the hERa AF-1 in a MAPK-mediated phosphorylationdependent manner. In this review, the molecular mechanism of this cross-talk is discussed in terms of the transactivation function of ERs, and their coactivators.

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“…Phosphorylations of ERa on serines 104, 106, 118 and 167, and tyrosine 537, have been shown by using deletional or point mutation analyses or by high-pressure liquid chromatography purification (Arnold et al, 1994;Le Goff et al, 1994;Castano et al, 1997;Deborah, 2003;Acconcia et al, 2006;Rayala et al, 2006). Mutation of serine 118 to alanine reduces ERa transcriptional activity (Joel et al, 1995), whereas mutation of tyrosine 537 leads to increased ligand-independent ERa transcriptional activation by affecting its DNA-binding ability and dimerization (Arnold et al, 1995(Arnold et al, , 1997. Phosphorylation of ERa at serine 118 is mediated by the RAS/MAPK pathway (Joel et al, 1995(Joel et al, , 1998Kato et al, 1995;Bunone et al, 1996), whereas phosphorylation of ERa at tyrosine 537 is mediated by members of the Src family of tyrosine kinases in vitro (Migliaccio et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Mutation of serine 118 to alanine reduces ERa transcriptional activity (Joel et al, 1995), whereas mutation of tyrosine 537 leads to increased ligand-independent ERa transcriptional activation by affecting its DNA-binding ability and dimerization (Arnold et al, 1995(Arnold et al, , 1997. Phosphorylation of ERa at serine 118 is mediated by the RAS/MAPK pathway (Joel et al, 1995(Joel et al, , 1998Kato et al, 1995;Bunone et al, 1996), whereas phosphorylation of ERa at tyrosine 537 is mediated by members of the Src family of tyrosine kinases in vitro (Migliaccio et al, 2000). Phosphorylation of ERa by casein kinase II and pp90rsk1 on serine 167 in vitro has also been shown (Kato et al, 1995;Chen et al, 1999;Clark et al, 2001;Hiroko et al, 2005;Senad et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

He¹,

Zheng²,

Song³

et al. 2010

Oncogene

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Estrogen receptors are members of the steroid hormone superfamily of nuclear receptors that act as ligandactivated transcription factors. Similar to other steroid hormone receptors, estrogen receptor a (ERa) is a substrate for protein kinases, and phosphorylation has profound effects on the function of this receptor. In this study, we show that ERa associates with c-Abl nonreceptor tyrosine kinase. The direct interaction is mediated by two PXXP motifs of ERa and the c-Abl SH3 domain. Mutational analysis and in vitro kinase assays show that ERa can be phosphorylated on two sites, tyrosine 52 (Y-52) and tyrosine 219 (Y-219). ERa phosphorylation by c-Abl stabilizes ERa, resulting in enhanced ERa transcriptional activity and increased expression of endogenous ERa target genes. Furthermore, ERa phosphorylation at the Y-219 site affects DNA binding and dimerization by ERa. Both the c-Abl inhibitor and the c-Abl kinase dead mutation abolish the c-Ablinduced accumulation of ERa and enhancement of ERa transcriptional activity, indicating that c-Abl kinase activity is required for regulation of the ERa function. Moreover, the ERa (Y52,219F) mutant shows reduced breast cancer cell growth and invasion. Taken together, these results show that c-Abl is a novel kinase that upregulates ERa expression and promotes breast cancer cell proliferation, suggesting a great potential for this kinase to function as a therapeutic target for breast cancer.

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Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor.

Cited by 69 publications

References 16 publications

Impact of PKCδ on estrogen receptor localization and activity in breast cancer cells

Impact of PKCδ on estrogen receptor localization and activity in breast cancer cells

Molecular mechanism of a cross‐talk between oestrogen and growth factor signalling pathways

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

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