Phosphoinositide 3-kinase-independent non-genomic signals transit from the androgen receptor to Akt1 in membrane raft microdomains
Phosphoinositide 3-kinase-independent non-genomic signals transit from the androgen receptor to Akt1 in membrane raft microdomains
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DOI：
10.1074/jbc.m703310200
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发表时间：
2007-10-05
影响因子：
4.8
通讯作者：
Freeman, Michael R.
中科院分区：
文献类型：
--
作者：
Cinar, Bekir;Mukhopadhyay, Nishit K.;Freeman, Michael R.
丝氨酸苏氨酸激酶，Akt1/蛋白激酶Bα是生长、存活和代谢信号的重要中介。最近的研究表明，富含胆固醇的脂筏微域与Akt1介导的生存信号有关。在这里，我们讨论了脂筏膜作为雄激素和Akt1信号的潜在交叉点的作用。雄激素受体(AR)的一个亚群被发现定位于LNCaP前列腺癌细胞的脂筏亚细胞室。内源性AR与内源性Akt1在脂筏组分中优先相互作用，雄激素显著增强两种蛋白之间的相互作用。AR与Akt1的结合可被抗雄激素比卡鲁胺抑制，但不受磷脂酰肌醇3-激酶(PI3K)抑制。雄激素在10分钟内以不依赖于PI3K的方式促进脂筏组分的内源性Akt1活性。脂筏靶向序列与AR的融合增强了受体在RAFT上的定位，并刺激了Akt1对雄激素的反应，同时减少了细胞对通过PI3K实现细胞生存的结构性信号的依赖。这些发现表明，通过AR和Akt1传递的信号通过一种机制相交，该机制涉及在脂筏膜内形成雄激素反应的核外AR/Akt1复合体。我们的结果表明，富含胆固醇的膜微区在前列腺癌细胞中传递涉及雄激素和Akt途径的非基因组信号方面发挥了作用。
The serine-threonine kinase, Akt1/protein kinase B alpha is an important mediator of growth, survival, and metabolic signaling. Recent studies have implicated cholesterol-rich, lipid raft microdomains in survival signals mediated by Akt1. Here we address the role of lipid raft membranes as a potential site of intersection of androgenic and Akt1 signaling. A subpopulation of androgen receptor (AR) was found to localize to a lipid raft subcellular compartment in LNCaP prostate cancer cells. Endogenous AR interacted with endogenous Akt1 preferentially in lipid raft fractions and androgen substantially enhanced the interaction between the two proteins. The association of AR with Akt1 was inhibited by the anti-androgen, bicalutamide, but was not affected by inhibition of phosphoinositide 3-kinase (PI3K). Androgen promoted endogenous Akt1 activity in lipid raft fractions, in a PI3K-independent manner, within 10 min of treatment. Fusion of a lipid raft targeting sequence to AR enhanced localization of the receptor to rafts, and stimulated Akt1 activity in response to androgen, while reducing the cells' dependence on constitutive signaling through PI3K for cell survival. These findings suggest that signals channeled through AR and Akt1 intersect by a mechanism involving formation within lipid raft membranes of an androgen-responsive, extranuclear AR/Akt1 complex. Our results indicate that cholesterol-rich membrane microdomains play a role in transmitting nongenomic signals involving androgen and the Akt pathway in prostate cancer cells.