Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling
Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling
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DOI：
10.1073/pnas.0504337103
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发表时间：
2006-03-21
影响因子：
11.1
通讯作者：
Emerson, CP
中科院分区：
文献类型：
--
作者：
Riobó, NA;Lu, K;Emerson, CP
Hedgehog (Hhs) 是胚胎干细胞维持和组织模式的关键信号调节因子，激活通路中增加 Gli 转录活性的突变是多种癌症的原因。在此，我们报告磷酸肌醇 3 激酶 (PI3 激酶) 依赖性 Akt 激活对于鸡神经外植体中神经元命运的规范、10T1/2 细胞的软骨分化和 NIH 3T3 细胞中的 Gli 激活中的 Sonic Hedgehog (Shh) 信号传导至关重要。胰岛素样生长因子 I 对 PI3 激酶/Akt 的刺激增强了低水平 Shh 诱导的 Gli 激活；然而，单独的胰岛素样生长因子 I 不足以诱导 Gli 依赖性转录。蛋白激酶 A (PKA) 和糖原合酶激酶 3 beta 在多个位点依次磷酸化 Gli2（通过诱变鉴定），从而导致其转录活性降低。 Gli2 突变蛋白，其中主要 PKA 和糖原合成酶激酶 3 β 磷酸化位点突变为丙氨酸，仍保持完全转录活性；然而，PKA 突变体 Gli2 的功能独立于 Akt 信号传导，表明 Akt 通过控制 PKA 介导的 Gli 失活来正向调节 Shin 信号传导。我们的研究结果为 PI3 激酶/Akt 在胚胎发育和 Hh 依赖性肿瘤的 Hh 信号传导中的协同作用提供了基础。
Hedgehogs (Hhs) are key signaling regulators of stem cell maintenance and tissue patterning in embryos, and activating mutations in the pathway that increase Gli transcriptional activity are causal in a diversity of cancers. Here, we report that phosphoinositide 3-kinase (PI3-kinase)-dependent Akt activation is essential for Sonic Hedgehog (Shh) signaling in the specification of neuronal fates in chicken neural explants, chondrogenic differentiation of 10T1/2 cells, and Gli activation in NIH 3T3 cells. Stimulation of PI3-kinase/Akt by insulin-like growth factor I potentiates Gli activation induced by low levels of Shh; however, insulin-like growth factor I alone is insufficient to induce Gli-dependent transcription. Protein kinase A (PKA) and glycogen synthase kinase 3 beta sequentially phosphorylate Gli2 at multiple sites, identified by mutagenesis, thus resulting in a reduction of its transcriptional activity. Gli2 mutant proteins in which the major PKA and glycogen synthase kinase 3 beta phosphorylation sites were mutated to alanine remain fully transcriptionally active; however, PKA-mutant Gli2 functions independently of Akt signaling, indicating that Akt positively regulates Shin signaling by controlling PKA-mediated Gli inactivation. Our findings provide a basis for the synergistic role of PI3-kinase/Akt in Hh signaling in embryonic development and Hh-dependent tumors.