mTORC1 介导的信号转导
中文名称
通路描述
mTORC1 整合了四种主要信号——生长因子、能量状态、氧气和氨基酸——来调节许多促进细胞生长的过程。生长因子通过激活经典的胰岛素和 Ras 信号通路刺激 mTORC1。细胞的能量状态通过 AMP 活化蛋白激酶 (AMPK) 传递到 mTORC1，AMPK 是细胞内能量状态的关键传感器 (Hardie 2007)。能量耗竭（低 ATP:ADP 比率）激活 AMPK，该激酶磷酸化 TSC2，增加其对 Rheb 的 GAP 活性，从而减少 mTORC1 的激活 (Inoki et al. 2003)。AMPK 可以通过直接磷酸化 Raptor 来减少 mTORC1 的活性 (Gwinn et al. 2008)。氨基酸正调节 mTORC1 (综述 Guertin & Sabatini 2007)。在有氨基酸存在的情况下，Rag 蛋白与 Raptor 结合，促进 mTORC1 从细胞质向溶酶体膜的重新定位 (Puertollano 2014)，在那里它由 Rheb 激活 (Saucedo et al. 2003, Stocker et al. 2003)。mTOR 向溶酶体的转位需要活跃的 Rag GTP 酶和一种称为 Ragulator 的复杂，这是一种五聚体蛋白复合物，将 Rag GTP 酶锚定在溶酶体上 (Sancak et al. 2008, 2010, Bar-Peled et al. 2012)。Rag 蛋白作为异二聚体发挥作用，由 GTP 结合的 RagA 或 RagB 复合物与 GDP 结合的 RagC 或 RagD 结合而成。氨基酸可能触发 RagA/B 的 GTP 装载，从而促进与 raptor 的结合并组装激活的 mTORC1 复合物，尽管最近的一项研究表明 mTORC1 的激活并不依赖于 Rag GTP 充电 (Oshiro et al. 2014)。Rheb 的活性由一种复合物调节，该复合物包括成纤维细胞生长因子 1 抑制复合物 (TSC1)、TSC2 和 TBC1 结构域家族成员 7 (TBC1D7) (Huang et al. 2008, Dibble et al. 2012)。该复合物定位于溶酶体，并作为 GTP 酶激活蛋白 (GAP) 发挥作用，抑制 Rheb 的活性 (Menon et al. 2014, Demetriades et al. 2014)。在有生长因子或胰岛素存在的情况下，TSC 释放其对 Rheb 的抑制活性，从而允许 mTORC1 的激活。
英文描述
mTORC1-mediated signalling mTORC1 integrates four major signals â growth factors, energy status, oxygen and amino acids â to regulate many processes that are involved in the promotion of cell growth. Growth factors stimulate mTORC1 through the activation of the canonical insulin and Ras signaling pathways. The energy status of the cell is signaled to mTORC1 through AMP-activated protein kinase (AMPK), a key sensor of intracellular energy status (Hardie 2007). Energy depletion (low ATP:ADP ratio) activates AMPK which phosphorylates TSC2, increasing its GAP activity towards Rheb which reduces mTORC1 activation (Inoki et al. 2003). AMPK can reduce mTORC1 activity by directly phosphorylating Raptor (Gwinn et al. 2008). Amino acids positively regulate mTORC1 (reviewed by Guertin & Sabatini 2007). In the presence of amino acids, Rag proteins bind Raptor to promote the relocalization of mTORC1 from the cytoplasm to lysosomal membranes (Puertollano 2014) where it is activated by Rheb (Saucedo et al. 2003, Stocker et al. 2003). Translocation of mTOR to the lysosome requires active Rag GTPases and a complex known as Ragulator, a pentameric protein complex that anchors the Rag GTPases to lysosomes (Sancak et al. 2008, 2010, Bar-Peled et al. 2012). Rag proteins function as heterodimers, consisting of GTP-bound RagA or RagB complexed with GDP-bound RagC or RagD. Amino acids may trigger the GTP loading of RagA/B, thereby promoting binding to raptor and assembly of an activated mTORC1 complex, though a recent study suggested that the activation of mTORC1 is not dependent on Rag GTP charging (Oshiro et al. 2014). The activity of Rheb is regulated by a complex consisting of tuberous sclerosis complex 1 (TSC1), TSC2, and TBC1 domain family member 7 (TBC1D7) (Huang et al. 2008, Dibble et al. 2012). This complex localizes to lysosomes and functions as a GTPase-activating protein (GAP) that inhibits the activity of Rheb (Menon et al. 2014, Demetriades et al. 2014). In the presence of growth factors or insulin, TSC releases its inhibitory activity on Rheb, thus allowing the activation of mTORC1.
所含基因
22 个基因