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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling
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Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling

机译：磷酸肌醇3-激酶和Akt对Sonic Hedgehog信号传导至关重要

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摘要

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 phosphoino-sitide 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 3β sequentially phosphorylate Gli2 at multiple sites, identified by mutagen-esis, thus resulting in a reduction of its transcriptional activity. Gli2 mutant proteins in which the major PKA and glycogen synthase kinase 3? phosphorylation sites were mutated to alanine remain fully transcriptionally active; however, PKA-mutant Gli2 functions independently of Akt signaling, indicating that Akt positively regulates Shh signaling by controlling PKA-mediated Gli inactiva-tion. Our findings provide a basis for the synergistic role of PI3-kinase, Akt in Hh signaling in embryonic development and Hh-dependent tumors.
机译：刺猬（Hhs）是胚胎中干细胞维持和组织模式的关键信号调节剂，而增加Gli转录活性的途径中的活化突变是多种癌症的起因。在这里，我们报告依赖磷酸肌醇3-激酶（PI3-激酶）的Akt激活对于鸡神经外植体的神经元命运，10T1 / 2细胞的软骨分化以及Gli的声波刺猬（Shh）信号传导至关重要在NIH 3T3细胞中激活。胰岛素样生长因子I刺激PI3激酶/ Akt增强了低水平Shh诱导的Gli激活。然而，仅胰岛素样生长因子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3β依次在多个位点上使Gli2磷酸化，该位点已通过诱变法鉴定，因此导致其转录活性降低。其中Gli2突变蛋白主要有PKA和糖原合酶激酶3′？磷酸化位点被突变为丙氨酸，保持完全转录活性；然而，PKA突变Gli2的功能独立于Akt信号传导，这表明Akt通过控制PKA介导的Gli失活而积极调节Shh信号传导。我们的发现为PI3-激酶，Akt在胚胎发育和Hh依赖性肿瘤中的Hh信号传导中的协同作用提供了基础。

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