Cell-to-cell variability in PI3K protein level regulates PI3K-AKT pathway activity in cell populations.
Cell-to-cell variability in PI3K protein level regulates PI3K-AKT pathway activity in cell populations.
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DOI：
10.1016/j.cub.2010.12.047
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发表时间：
2011-02-08
期刊：
影响因子：
9.2
通讯作者：
Cantley, Lewis C.
中科院分区：
文献类型：
--
作者：
Yuan, Tina L.;Wulf, Gerburg;Burga, Laura;Cantley, Lewis C.
在哺乳动物细胞中已广泛观察到种群中细胞间的可变性。这种异质性可能是随机事件造成的，也可能是通过监管过程有意维持的。在后一种情况下，异质性应该带来一种选择性优势，使整个人口受益。利用多色流式细胞术，我们发现了MCF10A细胞群体中PI3K活性的强烈异质性，这在以前被只测量群体平均的技术所掩盖。我们发现，AKT活性对EGF刺激的反应是双峰的，并与PI3K蛋白水平相关，因此只有高PI3K蛋白的细胞才能激活AKT。我们进一步表明，在细胞群体中，PI3K蛋白水平的异质性总是通过一个可以由细胞密度调节的降解/再合成周期来保持的。鉴于PI3K途径是癌症中最常见的上调途径之一，我们认为PI3K活性的异质性通过限制PI3K仅激活一小部分细胞而对正常组织有利。这可能有助于保护整个人群免受过度激活该途径的影响，这可能会导致细胞衰老或癌症。与此一致，我们表明p110α(H1047R和E545K)的致癌突变部分逃避了这一负调控，导致人群中AKT活性增加。
Cell-to-cell variability in populations has been widely observed in mammalian cells. This heterogeneity can result from random stochastic events or can be deliberately maintained through regulatory processes. In the latter case, heterogeneity should confer a selective advantage that benefits the entire population. Using multicolor flow cytometry, we have uncovered robust heterogeneity in PI3K activity in MCF10A cell populations, which had been previously masked by techniques that only measure population averages. We show that AKT activity is bimodal in response to EGF stimulation and correlates with PI3K protein level, such that only cells with high PI3K protein can activate AKT. We further show that heterogeneity in PI3K protein levels is invariably maintained in cell populations through a degradation/re-synthesis cycle that can be regulated by cell density. Given that the PI3K pathway is one of the most frequently upregulated pathways in cancer, we propose that heterogeneity in PI3K activity is beneficial to normal tissues by restricting PI3K activation to only a subset of cells. This may serve to protect the population as a whole from over-activating the pathway, which can lead to cellular senescence or cancer. Consistent with this, we show that oncogenic mutations in p110α (H1047R and E545K) partially evade this negative regulation, resulting in increased AKT activity in the population.
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