Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Survival / physiology
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Cells, Cultured
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DNA-Binding Proteins / metabolism*
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Estradiol / pharmacology
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Estrogen Receptor Modulators / pharmacology
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Estrogens / pharmacology*
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Female
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Humans
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Mammary Glands, Animal / cytology
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Mammary Glands, Animal / drug effects
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Mammary Glands, Animal / metabolism
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Mice
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Transcription Factors / metabolism*
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Tumor Cells, Cultured / drug effects
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p21-Activated Kinases
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Estrogen Receptor Modulators
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Estrogens
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FOXO1 protein, human
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Foxo1 protein, mouse
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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Transcription Factors
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Estradiol
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PAK1 protein, human
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Pak1 protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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p21-Activated Kinases