PI3K p110 alpha and p110 beta have differential effects on Akt activation and protection against oxidative stress-induced apoptosis in myoblasts.
PI3K p110 alpha and p110 beta have differential effects on Akt activation and protection against oxidative stress-induced apoptosis in myoblasts.
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DOI：
10.1038/cdd.2009.150
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发表时间：
2010-04
影响因子：
12.4
通讯作者：
Adamo, M. L.
中科院分区：
文献类型：
--
作者：
Matheny, R. W., Jr.;Adamo, M. L.
PI 3 K的催化亚基通过磷酸化肌醇脂质在生长因子信号传导和存活中起关键作用。我们发现PI 3 K Class IA p110α和p110β在成肌细胞中具有不同的功能。在H2 O2处理的细胞中，抑制p110α可降低IGF-I刺激的Akt活性，并阻止IGF-I介导的存活;相反，siRNA敲低p110β可增加IGF-I刺激的Akt活性。然而，抑制p110β催化活性并没有增加IGF-I刺激的Akt活性，这表明p110β蛋白相互作用而不是减少磷酸肌醇的产生。在p110β缺陷的成肌细胞中，Akt活性的增加与ERK激活的减少以及ERK依赖的IRS-1 636/639磷酸化有关，我们的发现表明与p110β催化功能无关，但与IGF-IR内吞作用有关。我们还报道了IGF-I通过一种需要p110α的机制保护成肌细胞免受H2 O2诱导的凋亡，但在Akt和ERK抑制的条件下可能不依赖于Akt或ERK。这些观察结果表明，p110α和p110β是必不可少的成肌细胞的生长和代谢。总之，我们的研究结果提供了新的证据，p110亚型的作用，促进细胞增殖和稳态，IGF-IR内化，并在反对凋亡。
Catalytic subunits of PI3K play a critical role in growth factor signaling and survival by phosphorylating inositol lipids. We found that PI3K Class IA p110α and p110β have distinct functions in myoblasts. Inhibition of p110α reduced IGF-I-stimulated Akt activity and prevented IGF-I-mediated survival in H2O2-treated cells; in contrast, siRNA knockdown of p110β increased IGF-I-stimulated Akt activity. However, inhibition of p110β catalytic activity did not increase IGF-I-stimulated Akt activity, suggesting a role for p110β protein interactions rather than decreased generation of phosphoinositides in this effect. Increased Akt activity in p110β-deficient myoblasts was associated with diminished ERK activation as well as ERK-dependent IRS-1 636/639 phosphorylation, findings we show to be independent of p110β catalytic function, but associated with IGF-IR endocytosis. We also report that IGF-I protects myoblasts from H2O2-induced apoptosis through a mechanism that requires p110α, but may be independent of Akt or ERK under conditions of Akt and ERK inhibition. These observations suggest that both p110α and p110β are essential for growth and metabolism in myoblasts. Overall, our results provide new evidence for the roles of p110 isoforms in promoting cellular proliferation and homeostasis, IGF-IR internalization, and in opposing apoptosis.
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