Mazumdar Abhijit, Kumar Rakesh
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
FEBS Lett. 2003 Jan 30;535(1-3):6-10. doi: 10.1016/s0014-5793(02)03846-2.
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.
在乳腺癌细胞中，p21激活激酶-1（Pak1）和雌二醇-雌激素受体α的激活可促进细胞存活。我们试图确定雌激素是否刺激Pak1信号通路。我们发现，雌激素以一种对磷脂酰肌醇3激酶不敏感的方式快速激活Pak1激酶活性。此外，雌激素以Pak1依赖的方式诱导细胞存活叉头转录因子FKHR在细胞质中磷酸化并定位于核周。此外，Pak1直接与FKHR相互作用并使其磷酸化。观察到的FKHR因磷酸化而从细胞核中排除，损害了FKHR在雌激素处理的细胞或表达催化活性Pak1的细胞中激活其含有FKHR结合基序（FRE）的靶标Fas配体启动子的能力。相反，Pak1的显性负性自抑制结构域（Pak氨基酸83-149）的表达促进了FKHR从FRE激活转录的能力。总之，这些结果确定了一条将雌激素作用与Pak1信号传导以及Pak1与FKHR联系起来的新信号通路，表明Pak1是雌激素细胞存活功能的重要介质。
