Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells.

Stimulation of p21-activated kinase-1 (Pak1) and estradiol-estrogen receptor-alpha in mammary cancer cells promotes cell survival. We sought to determine whether estrogen stimulates the Pak1 pathway. We found that estrogen rapidly activated Pak1 kinase activity in a phosphatidylinositol 3-kinase-insensitive manner. Furthermore, estrogen induced phosphorylation and perinuclear localization of the cell survival forkhead transcription factor FKHR in the cytoplasm in a Pak1-dependent manner. In addition, Pak1 directly interacted with FKHR and phosphorylated it. The noticed phosphorylation-dependent exclusion of FKHR from the nucleus impaired the ability of FKHR to activate its target Fas ligand promoter containing the FKHR binding motif (FRE) in cells treated with estrogen or expressing catalytically active Pak1. In contrast, expression of the dominant-negative auto-inhibitory domain of Pak1 (Pak amino acids 83-149) promoted the ability of FKHR to activate transcription from FRE. Together, these results identify a novel signaling pathway linking estrogen action to Pak1 signaling, and Pak1 to FKHR, suggesting that Pak1 is an important mediator of estrogen's cell survival functions.