CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor alpha by cAMP.
The estrogen receptor alpha (ERalpha) 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 ERalpha. Whereas the direct phosphorylation of ERalpha 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 ERalpha, and the interaction is necessary for cAMP activation of ERalpha. 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 ERalpha HBD. As a result, depending on the activating signal, ERalpha recruits different coactivator complexes to regulate alternate sets of target genes.
Carascossa
Sophie
S
Département de Biologie Cellulaire, Université de Genève, Sciences III, CH-1211 Genève 4, Switzerland.
Dudek
Peter
P
Cenni
Bruno
B
Briand
Pierre-André
PA
Picard
Didier
D
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology
D018931:Antineoplastic Agents, Hormonal; D053468:CARD Signaling Adaptor Proteins; D047628:Estrogen Receptor alpha; D008024:Ligands; D013629:Tamoxifen; D000242:Cyclic AMP; C426242:CARD11 protein, human; D006162:Guanylate Cyclase