Département de Biologie Cellulaire, Université de Genève, Sciences III, CH-1211 Genève 4, Switzerland.
Genes Dev. 2010 Apr 1;24(7):708-19. doi: 10.1101/gad.568410.
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.
雌激素受体 α（ERalpha）可被雌激素和多种其他细胞外信号作为转录因子激活。这种配体非依赖性激活的机制，特别是 cAMP 信号通路，在很大程度上仍然未知。我们现在填补了 cAMP 和 ERalpha 之间信号通路中的空白。虽然 cAMP 激活的蛋白激酶 A（PKA）直接磷酸化 ERalpha 是可有可无的，但 PKA 对共激活剂相关的精氨酸甲基转移酶 1（CARM1）的单一丝氨酸的磷酸化对于与未结合配体的激素结合域（HBD）的 ERalpha 的直接结合是必需且充分的，并且该相互作用是 cAMP 激活 ERalpha 所必需的。促进组成性相互作用的持续 PKA 活性可能导致乳腺癌对他莫昔芬的耐药性。结合和激活涉及 ERalpha HBD 的一个新的调节槽。因此，根据激活信号，ERalpha 招募不同的共激活复合物来调节不同的靶基因。
