CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor α by cAMP
- Département de Biologie Cellulaire, Université de Genève, Sciences III, CH-1211 Genève 4, Switzerland
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↵1 These authors contributed equally to this work.
Abstract
The estrogen receptor α (ERα) is activated as a transcription factor by both estrogen and a large variety of other extracellular signals. The mechanisms of this ligand-independent activation, notably by cAMP signaling, are still largely unknown. We now close the gap in the signaling pathway between cAMP and ERα. Whereas the direct phosphorylation of ERα by the cAMP-activated protein kinase A (PKA) is dispensable, the phosphorylation of the coactivator-associated arginine methyltransferase 1 (CARM1) by PKA at a single serine is necessary and sufficient for direct binding to the unliganded hormone-binding domain (HBD) of ERα, and the interaction is necessary for cAMP activation of ERα. Sustained PKA activity promoting a constitutive interaction may contribute to tamoxifen resistance of breast tumors. Binding and activation involve a novel regulatory groove of the ERα HBD. As a result, depending on the activating signal, ERα recruits different coactivator complexes to regulate alternate sets of target genes.
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Footnotes
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↵3 Corresponding author.
E-MAIL didier.picard{at}unige.ch; FAX 41-22-379-6928.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.568410.
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Supplemental material is available at http://www.genesdev.org.
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- Received November 18, 2009.
- Accepted February 15, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press