Supplementary Fig. S1 from The mTOR Signaling Pathway Interacts with the ER Stress Response and the Unfolded Protein Response in Cancer

Abstract

<p>Supplementary Fig. S1. The structure of mTOR complexes and overview of the PI3K/AKT/mTOR signaling pathway. The mTOR signaling pathway is implicated in a variety of major cellular processes, from cell growth to apoptosis. mTOR nucleates at least two distinct multi-protein complexes, mTORC1 and mTORC2. mTORC1 activation occurs in the response of growth factors through PI3K/Akt and RAS/MAPK pathways. Human mTOR can assemble at least two larges, physically, and functionally distinct polyprotein complexes, mTORC1, and mTORC2. mTORC1 and mTORC2 share several common proteins, including the catalytic subunit mTOR, mLST8 and DEPTOR, and Tel2/Tti1 complex. In addition, each complex has specific proteins. The activity of mTORC1 is regulated by multiple signals, including nutrient availability such as amino acids (leucine, arginine, and glutamine), intracellular energy level (Low ATP/High AMP), and extracellular growth factors such as insulin and cytokine receptors. A receptor-mediated activation of PI3K leads to PIP3 being produced from PIP2. PIP3 then promoted the recruitment of PDK1, AKT, and mTORC2 complex, facilitating the phosphorylation and full activation of AKT at Thr308 and Ser473 via PDK1 and mTORC2, respectively. Activated AKT phosphorylates TSC2 and induces the dissociation of TSC1 and TSC2 complex, which results in the dissociation of TSC2 from lysosomes and loss of their inhibitory action on RHEB/mTORC1 axis. Upon activation, mTOC1 promotes basic cellular events, including Cap-dependent translation, fatty acid synthesis, nucleoid acid synthesis, ribosomal biogenesis, metabolic reprogramming to support rapid cancer cell growth and survival, metastasis and invasion, and angiogenesis. mTORC2 has different subcellular localization and phosphorylates and activates AGC kinase family members, including AKT at Ser473 (AKT-pSer473), SGK, and PKC in response to upstream signals such as IGF1. Similar to mTORC1, PI3K acts as a critical regulator of mTORC2 by inducing the binding of mTORC2 to the ribosome. mTOR, mammalian/mechanistic target of rapamycin; PI3K, phosphatidylinositol 3-kinase; RAPTOR, Regulatory associated protein of mTOR; PRAS40, Proline-rich AKT substrate 40ku; mLST8, Mammalian LST8, also called G protein b-subunit like protein; DEPTOR, DEP domain-containing-mTOR interacting protein; Tel2, Telomere maintenance 2; Tti1, Tel2-interacting protein 1; RICTOR, Rapamycin insensitive companion of mTOR; mSIN1, mitogen-activated protein kinase-associated protein 1; PROTOR, Protein observed with Rictor; SGK, serum glucose kinase; PKC, protein kinase C; IGF1; Insulin-like growth factor 1; AMPK, AMP-activated protein kinase; REDD1, regulated in development and DNA damage response 1; HIF-1α, hypoxia-inducible factor-1α; VEGF, vascular endothelial growth factor; PTEN, phosphatase and tensin homolog deleted on chromosome 10; NF-κB, nuclear factor-κB; ULK1, UNC-51-like kinase 1; 4E-BP1, initiation factor 4E-binding protein 1; RHEB, Ras homolog enriched in brain; TSC1 and TSC2, tuberous sclerosis proteins 1 and 2; GSK3β, glycogen synthase kinase 3β; MMP, matrix metallopeptidase; FKBP12, FK506-binding protein; PIP2, phosphatidylinositol 4,5 biphosphate; PDK1, phosphoinositol-dependent-kinase; PtdIns(3,4,5)P3, Phosphatidylinositol (3,4,5)-trisphosphate.</p>