Formation of an hERα–COUP-TFI complex enhances hERα AF-1 through Ser118 phosphorylation by MAPK

The enhancement of the human estrogen receptor α (hERα, NR3A1) activity by the orphan nuclear receptor COUP-TFI is found to depend on the establishment of a tight hERα–COUP-TFI complex. Formation of this complex seems to involve dynamic mechanisms different from those allowing hERα homodimerization. Although the hERα–COUP-TFI complex is present in all cells tested, the transcriptional cooperation between the two nuclear receptors is restricted to cell lines permissive to hERα activation function 1 (AF-1). In these cells, the physical interaction between COUP-TFI and hERα increases the affinity of hERα for ERK2/p42(MAPK), resulting in an enhanced phosphorylation state of the hERα Ser118. hERα thus acquires a strengthened AF-1 activity due to its hyperphosphorylation. These data indicate an alternative interaction process between nuclear receptors and demonstrate a novel protein intercommunication pathway that modulates hERα AF-1.