Phosphatidylinositol 3-kinase-Akt pathway plays a critical role in early cardiomyogenesis by regulating canonical Wnt signaling
Phosphatidylinositol 3-kinase-Akt pathway plays a critical role in early cardiomyogenesis by regulating canonical Wnt signaling
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DOI：
10.1161/01.res.0000175241.92285.f8
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发表时间：
2005-07-22
影响因子：
20.1
通讯作者：
Komuro, I
中科院分区：
文献类型：
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作者：
Naito, AT;Akazawa, H;Komuro, I
我们最近报道，磷脂酰肌醇3-激酶(PI3K)的激活在P19CL6细胞的早期分化过程中起着关键作用。我们在这里研究了PI3K如何参与心肌细胞分化的分子机制。DNA芯片分析显示，在P19CL6细胞分化的早期，Wnt-3a的表达水平明显升高，Wnt/β-catenin通路被暂时激活。在此期间，Wnt/β-catenin通路的激活是P19CL6细胞向心肌细胞分化所必需的，也是充分的。抑制PI3K/Akt通路通过激活糖原合成酶-3β(GSK-3β)和降解β-catenin来抑制Wnt/β-catenin通路。通过抑制PI3K/Akt途径抑制心肌细胞分化，可以通过强制表达一种非磷酸化的、结构性的活性形式的β-连环蛋白来挽救。这些结果提示，PI3K通路通过抑制GSK-3β活性和维持Wnt/β-catenin活性来调节心肌细胞分化。
We have recently reported that activation of phosphatidylinositol 3-kinase (PI3K) plays a critical role in the early stage of cardiomyocyte differentiation of P19CL6 cells. We here examined molecular mechanisms of how PI3K is involved in cardiomyocyte differentiation. DNA chip analysis revealed that expression levels of Wnt-3a were markedly increased and that the Wnt/beta-catenin pathway was activated temporally during the early stage of cardiomyocyte differentiation of P19CL6 cells. Activation of the Wnt/beta-catenin pathway during this period was required and sufficient for cardiomyocyte differentiation of P19CL6 cells. Inhibition of the PI3K/Akt pathway suppressed the Wnt/beta-catenin pathway by activation of glycogen synthase kinase-3 beta (GSK-3 beta) and degradation of beta-catenin. Suppression of cardiomyocyte differentiation by inhibiting the PI3K/Akt pathway was rescued by forced expression of a nonphosphorylated, constitutively active form of beta-catenin. These results suggest that the PI3K pathway regulates cardiomyocyte differentiation through suppressing the GSK-3 beta activity and maintaining the Wnt/beta-catenin activity.