Challenging estrogen receptor β with phosphorylation

Sanchez, Mélanie; Picard, Nathalie; Sauvé, Karine; Tremblay, André

doi:10.1016/j.tem.2009.09.007

Cited by 41 publications

(43 citation statements)

References 60 publications

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“…Nevertheless, our data clearly indicate that both c-ABL and EYA2 exert their opposing actions on the antitumor activity of ERβ primarily through Y36. Previous work has also implicated certain phosphoserine residues of ERβ in the regulation of ERβ transcriptional activity (41)(42)(43)(44)(45). It will be of interest to determine whether p-Y36 and the previously identified modification events can act cooperatively or antagonistically to regulate ERβ activity in the transcription and…”

Section: Discussionmentioning

confidence: 94%

A phosphotyrosine switch determines the antitumor activity of ERβ

Yuan¹,

Cheng²,

Chiang³

et al. 2014

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 94%

A phosphotyrosine switch determines the antitumor activity of ERβ

Yuan¹,

Cheng²,

Chiang³

et al. 2014

J. Clin. Invest.

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“…The short form of ERb1 may not be regulated by PES1 in the same way as the long form. Therefore, differential posttranslational modifications may affect ERb1 function including specific degradation pathways (Sanchez et al 2010, 2012, Cheng et al 2012) and kinetics of turnover, involving particular heterodimers for example, and contribute to a bi-faceted mechanism of action.…”

Section: Endocrine-related Cancermentioning

confidence: 99%

A bi-faceted role of estrogen receptor β in breast cancer

Leygue¹,

Murphy²

2013

Endocrine-Related Cancer

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Despite over 15 years of research, the exact role, if any, played by estrogen receptor b (ERb) in human breast cancer remains elusive. A large body of data both in vitro and in vivo supports its role as an antiproliferative, pro-apoptotic factor especially when co-expressed with ERa. However, there is a smaller body of data associating ERb with growth and survival in breast cancer. In clinical studies and most often in cell culture studies, the pro-growth and prosurvival activity of ERb occurs in ERa-negative breast cancer tissue and cells. This bi-faceted role of ERb is discussed in this review.

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“…For ERs, both ligand-induced and ligand-independent activation can be modulated by phosphorylation, in support of a significant role of kinase transduction pathways in differential signaling of ER␣ and ER␤ (28,39,50). More precisely, a cluster of phosphorylation sites has been identified to regulate activation function 1 (AF-1) activity of ER␤ and specific recruitment of coactivators SRC-1 and CBP and of ubiquitin ligase E6-AP, highlighting the key role of this modification in regulation of receptor activity and degradation (31,36,45). Sumoylation has recently been added as a new regulator in the fine-tuning of nuclear receptors and associated coregulator activities (48).…”

mentioning

confidence: 91%

Identification of Estrogen Receptor β as a SUMO-1 Target Reveals a Novel Phosphorylated Sumoylation Motif and Regulation by Glycogen Synthase Kinase 3β

Picard¹,

Caron²,

Bilodeau³

et al. 2012

Molecular and Cellular Biology

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c SUMO conjugation has emerged as a dynamic process in regulating protein function. Here we identify estrogen receptor ␤ (ER␤) to be a new target of SUMO-1. ER␤ SUMO-1 modification occurs on a unique nonconsensus sumoylation motif which becomes fully competent upon phosphorylation of its contained serine residue, which provides the essential negative charge for sumoylation. This process is further regulated by phosphorylation of additional adjacent serine residues by glycogen synthase kinase 3␤ (GSK3␤), which maximizes ER␤ sumoylation in response to hormone. SUMO-1 attachment prevents ER␤ degradation by competing with ubiquitin at the same acceptor site and dictates ER␤ transcriptional inhibition by altering estrogen-responsive target promoter occupancy and gene expression in breast cancer cells. These findings uncovered a novel phosphorylated sumoylation motif (pSuM), which consists of the sequence KXS (where represents a large hydrophobic residue) and which is connected to a GSK3-activated extension that functions as a SUMO enhancer. This extended pSuM offers a valuable signature to predict SUMO substrates under protein kinase regulation. Sumoylation is a highly dynamic posttranslational process that consists of conjugation of the small ubiquitin-like modifier SUMO on target proteins (20). SUMO modification is involved in diverse aspects of protein function which are often linked to nuclear activities, such as DNA replication, genome stability, nuclear transport, and gene transcription (41). Despite a low and transient stoichiometric proportion of SUMO-modified proteins, an increasing number of substrates have been characterized mostly on the basis of the presence of a predicted minimal core SUMO consensus motif, KXE/D (where represents a large hydrophobic residue), in which the lysine serves as the acceptor site to covalently link SUMO (35). The sequential enzymatic events leading to protein sumoylation closely resemble those of ubiquitination (13). The core SUMO motif is recognized by the unique 17␤-estradiol (E2)-conjugating enzyme Ubc9, which upon transfer from E1-activating enzyme 1 (SAE1)/SAE2 conjugates SUMO onto a specific lysine residue. Although Ubc9 is sufficient to promote sumoylation, three classes of E3 ligases that consist of the nucleoporin RanBP2, the polycomb repressor Pc2, and the PIAS ligase family members have been described to facilitate the conjugation process. Sumoylation is reversible, as the SUMO tags can rapidly be cleaved from target proteins by the SENP family of sentrin-specific isopeptidases, which ensure the dynamic and appropriate maintenance of SUMO substrates (24). Recently, two different extensions following the KXE/D motif have been found to enhance substrate sumoylation for some targets: the phosphorylation-dependent sumoylation motif (PDSM), which consists of the sequence KXEXXpSP (21), and the negatively charged amino acid-dependent sumoylation motif (NDSM), which is characterized by a cluster of acidic residues (51). As both motifs share a feature of negatively charged ...

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Challenging estrogen receptor β with phosphorylation

Cited by 41 publications

References 60 publications

A phosphotyrosine switch determines the antitumor activity of ERβ

A phosphotyrosine switch determines the antitumor activity of ERβ

A bi-faceted role of estrogen receptor β in breast cancer

Identification of Estrogen Receptor β as a SUMO-1 Target Reveals a Novel Phosphorylated Sumoylation Motif and Regulation by Glycogen Synthase Kinase 3β

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