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.[1]References
- Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells. Mazumdar, A., Kumar, R. FEBS Lett. (2003) [Pubmed]
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