https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904989/
mTORC1 is regulated by amino acids, growth factors (i.e., insulin), and energy status (AMP:ATP). Amino acids are sensed by the ragulator complex and the rag GTPases, mediating re-localization of mTORC1 to lysosomes where it encounters rheb. Insulin activates the IR, which then activates the IRS. Active IRS induces PI3K, which converts PIP2 to PIP3. PIP3 accumulation results in the recruitment of PDK1 and Akt to the plasma membrane where Akt is activated by PDK1. Akt phosphorylates and inhibits the TSC1–TSC2 complex, which inhibits rheb. Akt also inhibits the FoxO1/3A transcription factors转录因子, which positively regulate apoptosis. AMPK is activated by a high AMP:ATP ratio and inhibits mTORC1 by activating TSC1–TSC2 as well as by direct phosphorylation of the mTORC1 component raptor. Activation of mTORC1 inhibits IRS and Grb10 (not shown), resulting in negative feedback regulation of the PI3K–Akt branch. mTORC1 hyperactivation can lead to ER stress, which can activate or inhibit the TSC1–TSC2 complex. In addition, ER stress induces ATF4 translation, which can induce expression of the negative Akt regulator TRB3. Hypoxia also induces ATF4 translation, and activates AMPK. Induction of HIFs by hypoxia (via ATM) induces expression of REDD1, which activates the TSC1–TSC2 complex, inhibiting mTORC1. This results in a negative feedback loop, as mTORC1 controls REDD1 stability. Oxidative stress inhibits the tumor suppressors PTEN, and inhibits or activates TSC1–TSC2. Furthermore, oxidative stress can activate ATM and AMPK, both of which inhibit mTORC1. Tumor suppressors抑癌基因 are framed in green. Stress inputs are shown in red.
Hyperactive metabolic signaling (e.g., induced by oncogenes) can result in increased synthesis of proteins, RNA, DNA, and membranes. Lipid脂质 synthesis is required for ER homeostasis内质网稳态, whereas hyperactive protein synthesis can induce ER stress. Tumors eventually outgrow过大而不适于 the vascular system血管系统, leading to a shortage in glucose, oxygen, and building blocks (amino acids, nucleotides核苷酸, lipids). Glucose is required for ATP synthesis and is a carbon source for building block synthesis. Lack of ATP and building blocks inhibits lipid biosynthesis and chaperone activity分子伴侣活性. Therefore, ATP depletion enhances ER stress. Oxygen is required for ATP synthesis, and oxygen depletion results in hypoxia. ROS induce oxidative stress and originate from dysfunctions in mitochondria线粒体机能障碍, for example triggered by oncogenic signaling and mtDNA damage, respiratory chain imbalances, and lipid and protein biosynthesis. ER stress, hypoxia, and oxidative stress induce stress responses to restore cellular homeostasis细胞的自动调节, and eventually trigger apoptosis. Cancer cells have protective mechanisms to prevent the induction of apoptosis by chronic stresses慢性压力. Examples of such mechanisms are metabolic transformation (the Warburg effect瓦博格效应：namely aerobic glycolysis有氧糖酵解 and accumulation of lactate乳酸积累，Cells that exhibit the Warburg effect consume glucose relatively rapidly and therefore require a sufficient supply of glucose), glucose uptake, chaperone and antioxidant protein 抗氧化蛋白synthesis, autophagy, angiogenesis血管生成, and stress granule formation压力颗粒形成.
内质网应激（ER stress）表现为内质网腔内错误折叠与未折叠蛋白聚集以及钙离子平衡紊乱 ,可激活未折叠蛋白反应、内质网超负荷反应和 caspase-12 介导的凋亡通路等信号途径 ,既能诱导糖调节蛋白 (glucose2regulated protein 78 kD , GRP78) 、GRP94 等内质网分子伴侣表达而产生保护效应 ,亦能独立地诱导细胞凋亡。 内质网应激直接影响应激细胞的转归 ,如适应、损伤或凋亡。
https://baike.baidu.com/item/%E5%86%85%E8%B4%A8%E7%BD%91%E5%BA%94%E6%BF%80/6547388?fr=aladdin
The ULK1 complex (ULK1, ATG13, ATG101, and FIP200) and the Bcl-2–Beclin 1 complex are major autophagy regulators.
Autophagy can be divided into 3 different steps:
(1) phagophore formation吞噬物形成 and enlargement (autophagosome自噬体);
(2) lysosomal docking溶酶体对接 and fusion with the autophagosome (autolysosome自溶酶体);
(3) degradation of proteins and organelles胞器 in the autolysosome.
The ULK1 complex is needed for autophagy initiation, whereas assemble of the Bcl-2–Beclin 1 complex prevents Beclin 1 from triggering autophagy. The ULK1 complex is inhibited by mTORC1 and activated by AMPK. AMPK also directly inhibits mTORC1. ER stress induces ATF4, which controls transcription of stress factors such as TRB3, which is a negative effector upstream of mTORC1 (Akt inhibition). In addition, ATF4 has a positive effect on the ULK1 complex. ER stress activates Ire1 kinase, which induces JNK1, leading to disassembly分解 of the Bcl-2–Beclin 1 complex. Hypoxia also induces ATF4 expression and activates AMPK. In addition, hypoxia induces autophagy by BNIP3/BNIP3L-dependent disassembly of the Bcl-2–Beclin 1 complex. Oxidative stress induces autophagy in an AMPK-dependent manner.
Under non-stressed conditions DYRK3 phosphorylates and inactivates the mTORC1 inhibitor PRAS40. Active mTORC1 inhibits 4E‑BP1, allowing for eIF4F–5´cap–mRNA complex formation, ribosomal binding核糖体绑定, and translation initiation翻译起始.
Stressed conditions induce translational arrest, polysome disassembly多核糖体拆卸, and SG formation. mTORC1 is disassembled拆散, and the mTORC1 components mTOR and raptor are recruited to SGs. Kinase-inactive DYRK3 localizes through its N-terminus to SGs, where it promotes SG stability and prevents mTOR release. Astrin binds to raptor and recruits it to SGs, thereby mediating SG-dependent mTORC1 disassembly. mTORC1 inactivation results in induction of autophagy, which is required for SG clearance after stress release and for SG formation. However, inhibition of 4E-BP1 by mTORC1 is required for SG formation, as 5´cap–eIF4F complexes and binding of the 40S ribosomal subunit are required for SG formation. Thus, SGs restrict mTORC1 activity, but some mTORC1 activity is needed for SG assembly (indicated by dashed arrows).
Black arrows represent active connections, gray arrows represent inactive connections in stressed versus non-stressed cells.
SGs, in contrast, are likely to be more essential for cancer cells than for healthy tissues to overcome a stressed cellular environment. Thus, SG modulation represents a promising orthogonal approach to complement existing therapies involving targeted drugs or chemotherapeutics.