PI3K/Akt signaling requires spatial compartmentalization in plasma membrane microdomains
PI3K/Akt signaling requires spatial compartmentalization in plasma membrane microdomains
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DOI：
10.1073/pnas.1019386108
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发表时间：
2011-08-30
影响因子：
11.1
通讯作者：
Zhang, Jin
中科院分区：
文献类型：
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作者：
Gao, Xinxin;Lowry, Pamela R.;Zhang, Jin
信号通路组分的空间区室化通常定义了特异性并增强了信号转导的效率。已知磷脂酰肌醇3-激酶（PI 3 K）/Akt通路在质膜微域内被区室化;然而，这种区室化的潜在机制和功能影响尚未得到很好的理解。在这里，我们表明，磷酸肌醇依赖性激酶1被激活的膜筏在响应生长因子，而负调节的途径，磷酸酶和张力蛋白同源物10号染色体上删除（PTEN），主要定位在nonraft地区。这种区室化的改变，无论是通过基因靶向或神经酰胺诱导的招募PTEN筏，废除整个途径的活动。这些发现揭示了筏介导的PI 3 K/Akt激活的关键步骤，并证明了膜微区室化在实现PI 3 K/Akt信号传导中的重要作用。他们进一步表明，这种区室化的失调可能是病理并发症如胰岛素抵抗的基础。
Spatial compartmentalization of signaling pathway components generally defines the specificity and enhances the efficiency of signal transduction. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is known to be compartmentalized within plasma membrane microdomains; however, the underlying mechanisms and functional impact of this compartmentalization are not well understood. Here, we show that phosphoinositide-dependent kinase 1 is activated in membrane rafts in response to growth factors, whereas the negative regulator of the pathway, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), is primarily localized in nonraft regions. Alteration of this compartmentalization, either by genetic targeting or ceramide-induced recruitment of PTEN to rafts, abolishes the activity of the entire pathway. These findings reveal critical steps in raft-mediated PI3K/Akt activation and demonstrate the essential role of membrane microdomain compartmentalization in enabling PI3K/Akt signaling. They further suggest that dysregulation of this compartmentalization may underlie pathological complications such as insulin resistance.