Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Cell Death Differ. 2010 Apr;17(4):677-88. doi: 10.1038/cdd.2009.150. Epub 2009 Oct 16.
Catalytic subunits of phosphoinositide-3-kinase (PI3K) play a critical role in growth factor signaling and survival by phosphorylating inositol lipids. We found that PI3K Class-IA p110 alpha and p110 beta have distinct functions in myoblasts. Inhibition of p110 alpha reduced insulin-like growth factor-I (IGF-I)-stimulated Akt activity and prevented IGF-I-mediated survival in H(2)O(2)-treated cells; in contrast, siRNA knockdown of p110 beta increased IGF-I-stimulated Akt activity. However, inhibition of p110 beta catalytic activity did not increase IGF-I-stimulated Akt activity, suggesting a role for p110 beta protein interactions rather than decreased generation of phosphoinositides in this effect. Increased Akt activity in p110 beta-deficient myoblasts was associated with diminished extracellular signal-regulated kinase (ERK) activation as well as ERK-dependent IRS-1 636/639 phosphorylation, findings we show to be independent of p110 beta catalytic function, but associated with insulin-like growth factor-I receptor (IGF-IR) endocytosis. We also report that IGF-I protects myoblasts from H(2)O(2)-induced apoptosis through a mechanism that requires p110 alpha, but may be independent of Akt or ERK under conditions of Akt and ERK inhibition. These observations suggest that both p110 alpha and p110 beta 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.
磷酸肌醇-3-激酶（PI3K）的催化亚基通过磷酸化肌醇脂质在生长因子信号转导和存活中起关键作用。我们发现，PI3K 类-I p110α 和 p110β 在成肌细胞中有不同的功能。p110α 的抑制降低了胰岛素样生长因子-I（IGF-I）刺激的 Akt 活性，并阻止了 H2O2 处理细胞中 IGF-I 介导的存活；相比之下，p110β 的 siRNA 敲低增加了 IGF-I 刺激的 Akt 活性。然而，抑制 p110β 的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这种效应中起作用。p110β 缺陷型成肌细胞中 Akt 活性的增加与细胞外信号调节激酶（ERK）激活以及 ERK 依赖性 IRS-1 636/639 磷酸化减少有关，我们的研究结果表明这与 p110β 的催化功能无关，但与胰岛素样生长因子-I 受体（IGF-IR）内化有关。我们还报告，IGF-I 通过一种需要 p110α 的机制保护成肌细胞免受 H2O2 诱导的凋亡，但在 Akt 和 ERK 抑制的情况下，可能独立于 Akt 或 ERK。这些观察结果表明，p110α 和 p110β 对于成肌细胞的生长和代谢都是必不可少的。总的来说，我们的研究结果为 p110 同工型在促进细胞增殖和稳态、IGF-IR 内化以及拮抗凋亡中的作用提供了新的证据。
