mTOR磷酸化组学

The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling.

---

|核心内容：

哺乳动物雷帕霉素靶蛋白激酶(mTOR)是一个主要的细胞生长推动者，在哺乳动物体内形成 mTORC1和 mTORC2两个复合物。尽管 mTOR 控制的下游底物多种多样，但是现在我们知道的下游底物还很少。我们定义了 mTOR 调控的磷酸化蛋白质组，并利用定位扫描肽库表征了 mTOR 的一级序列特异性。我们发现胰岛素介导的磷酸化反应很大程度上依赖于 mTOR，而且 mTOR 在 + 1位置表现出对脯氨酸、疏水性和芳香族残基的独特偏好。在缺乏mTORC1负性调节剂 TSC2的细胞中，mTORC1活性大幅度上调，在这个细胞系中接头蛋白 Grb10被鉴定为 mTORC1底物，介导磷脂酰肌醇3激酶（PI3K)的抑制作用。我们的工作澄清了 mTORC1如何抑制生长因子信号转导，并开辟了 mTOR 生物学研究的新领域。

mTORC1抑制胰岛素介导的PI3K通路

原文摘要：

The mammalian target of rapamycin (mTOR) protein kinase is a master growth promoter that nucleates two complexes, mTORC1 and mTORC2. Despite the diverse processes controlled by mTOR, few substrates are known. We defined the mTOR-regulated phosphoproteome by quantitative mass spectrometry and characterized the primary sequence motif specificity of mTOR using positional scanning peptide libraries. We found that the phosphorylation response to insulin is largely mTOR dependent and that mTOR exhibits a unique preference for proline, hydrophobic, and aromatic residues at the +1 position. The adaptor protein Grb10 was identified as an mTORC1 substrate that mediates the inhibition of phosphoinositide 3-kinase typical of cells lacking tuberous sclerosis complex 2 (TSC2), a tumor suppressor and negative regulator of mTORC1. Our work clarifies how mTORC1 inhibits growth factor signaling and opens new areas of investigation in mTOR biology.

雷帕霉素或Torin1的长期处理阻断mTORC1对PI3K通路的抑制

参考文献：https://dx.doi.org/10.1126/science.1199498

-------------------------------------------------------------------------