P21-Activated Kinase 1 Regulation of Estrogen Receptor-α Activation Involves Serine 305 Activation Linked with Serine 118 Phosphorylation

Abstract

Here, we investigated the role of P21-activated kinase 1 (Pak1) signaling in the function of estrogen receptor-A (ER-A) as assessed by serine 305 (S305) activation and transactivation activity of ER. We found that Pak1 overexpression interfered with the antiestrogenic action of tamoxifen upon the ER transactivation function in hormone-sensitive cells. In addition, tamoxifen stimulation led to up-regulation of ER target genes in breast cancer cells with increased Pak1 expression. Tamoxifen also increased Pak1-ER interaction in tamoxifenresistant but not in tamoxifen-sensitive cells. Results from the mutational studies discovered a role of ER-S305 phosphorylation in triggering a subsequent phosphorylation of serine 118 (S118), and these effects were further potentiated by tamoxifen treatment. We found that S305 activation-linked ER transactivation function requires a functional S118, and active Pak1 signaling is required for a sustaining S118 phosphorylation of the endogenous ER. All of these events were positively influenced by tamoxifen and thus may contribute toward the loss of antiestrogenic effect of tamoxifen. These findings suggest that Pak1 signaling-dependent activation of ER-S305 leads to an enhanced S118 phosphorylation presumably due to a conformational change, and such structural modifications may participate in the development of tamoxifen resistance.

Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer

“…Balasenthil et al (2004a) showed that activation of the receptor by an amino-acid switch (S305E) upregulates the expression of cyclin D1. Opposite to results from in vitro studies (Holm et al, 2006;Rayala et al, 2006b), we found no correlation between pak1 and cyclin D1 protein expression. Nor could this link be shown in the ER-positive tumor group.…”

“…This indicates that amplification of the assessed genes confers selective advantage in the tumorigenesis of ERpositive breast cancer. Several studies show that the pak1 protein interacts with the ER (Wang et al, 2002;Balasenthil et al, 2004a;Rayala et al, 2006b). Also, the cyclin D1 protein has been shown to form a complex with the ER and thereby activating its transactivating functions in the absence of estradiol (Neuman et al, 1997).…”

“…Experimental studies have recently shown increasing evidence for the cyclin D1 and pak1 connection to tamoxifen response (Hodges et al, 2003;Holm et al, 2006;Rayala et al, 2006b). For that reason, we sought to analyse the association of these two genes with tamoxifen resistance in a clinical material.…”

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

“…Regulation of gene expression by ERa requires the coordinate activity of ligand binding, phosphorylation and cofactor interactions. Phosphorylations of ERa on serines 104, 106, 118 and 167, and tyrosine 537, have been shown by using deletional or point mutation analyses or by high-pressure liquid chromatography purification (Arnold et al, 1994;Le Goff et al, 1994;Castano et al, 1997;Deborah, 2003;Acconcia et al, 2006;Rayala et al, 2006). Mutation of serine 118 to alanine reduces ERa transcriptional activity (Joel et al, 1995), whereas mutation of tyrosine 537 leads to increased ligand-independent ERa transcriptional activation by affecting its DNA-binding ability and dimerization (Arnold et al, 1995(Arnold et al, , 1997.…”

Les modifications post-traductionnelles orchestrent l’action du récepteur des œstrogènes εRα dans les tumeurs mammaires

“…Par exemple, une relation fonctionnelle a été mise en évidence entre la phosphorylation de la sérine 305, celle de la sérine 118 et l'acétylation de la lysine 303. La mutation de la sérine 305 en acide glutamique, qui mime une phosphorylation constitutive, conduit à une augmentation de la phosphorylation de la sérine 118 et à une inhibition de l'acéty lation de la lysine 303 [20]. La phosphorylation de la sérine 305 par Pak1 est donc nécessaire au maintien de la phosphorylation de la sérine 118 et à l'inhibition de l'acétylation de la lysine 303, poten tialisant ainsi l'activité transcriptionnelle de ER [21].…”