ERα phosphorylation at Y537 by Src triggers E6-AP-ERα binding, ERα ubiquitylation, promoter occupancy, and target gene expression

Jun Sun, Wen Zhou, Kosalai Kaliappan, Zafar Nawaz, Joyce M Slingerland

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Many transcription factors undergo transcription-coupled proteolysis. Although ligand binding activates ubiquitin proteolysis of estrogen receptor α (ERα), mechanisms governing this and its relationship to transcriptional activation were unclear. Data presented link cross talk between the Src kinase and liganded ERα with ERα activation and its ubiquitylation. Liganded ERα rapidly activates and recruits Src, which phosphorylates ERα at tyrosine 537 (Y537). This enhances ERα binding to the ubiquitin ligase/ERα coactivator, E6-associated protein (E6-AP), stimulating ERα ubiquitylation, target gene activation, and ultimately ERα loss. ERα phosphorylation by Src promotes ERα ubiquitylation by E6-AP and proteasomal degradation in vitro. Src inhibition impairs estrogen (E2)-activated ERα:E6-AP binding, reducing ERα degradation. ERα-Y537F shows little E2-stimulated degradation and activates native ERα target genes poorly. Src activation enhances ERα and E6-AP binding and their occupancy at ERα target gene promoters to enhance transcription. Thus, ERαY537 phosphorylation drives ERα:E6-AP binding to at least a subset of target promoters, linking transcriptional activation to ERα degradation and providing a novel mechanism to fine tune ERα action. The observation that ERα transcriptional activity can be briskly maintained in a context of reduced ERα levels raises the possibility that hormonally sensitive tissues may not always show robust ERα protein levels.

Original languageEnglish
Pages (from-to)1567-1577
Number of pages11
JournalMolecular Endocrinology
Volume26
Issue number9
DOIs
StatePublished - Sep 1 2012

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Ubiquitination
Estrogen Receptors
Phosphorylation
Gene Expression
estrophilin
Protein Binding
Transcriptional Activation
Proteolysis
Ubiquitin

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

ERα phosphorylation at Y537 by Src triggers E6-AP-ERα binding, ERα ubiquitylation, promoter occupancy, and target gene expression. / Sun, Jun; Zhou, Wen; Kaliappan, Kosalai; Nawaz, Zafar; Slingerland, Joyce M.

In: Molecular Endocrinology, Vol. 26, No. 9, 01.09.2012, p. 1567-1577.

Research output: Contribution to journalArticle

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abstract = "Many transcription factors undergo transcription-coupled proteolysis. Although ligand binding activates ubiquitin proteolysis of estrogen receptor α (ERα), mechanisms governing this and its relationship to transcriptional activation were unclear. Data presented link cross talk between the Src kinase and liganded ERα with ERα activation and its ubiquitylation. Liganded ERα rapidly activates and recruits Src, which phosphorylates ERα at tyrosine 537 (Y537). This enhances ERα binding to the ubiquitin ligase/ERα coactivator, E6-associated protein (E6-AP), stimulating ERα ubiquitylation, target gene activation, and ultimately ERα loss. ERα phosphorylation by Src promotes ERα ubiquitylation by E6-AP and proteasomal degradation in vitro. Src inhibition impairs estrogen (E2)-activated ERα:E6-AP binding, reducing ERα degradation. ERα-Y537F shows little E2-stimulated degradation and activates native ERα target genes poorly. Src activation enhances ERα and E6-AP binding and their occupancy at ERα target gene promoters to enhance transcription. Thus, ERαY537 phosphorylation drives ERα:E6-AP binding to at least a subset of target promoters, linking transcriptional activation to ERα degradation and providing a novel mechanism to fine tune ERα action. The observation that ERα transcriptional activity can be briskly maintained in a context of reduced ERα levels raises the possibility that hormonally sensitive tissues may not always show robust ERα protein levels.",
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