Supplementary Fig. S2 from The mTOR Signaling Pathway Interacts with the ER Stress Response and the Unfolded Protein Response in Cancer

Supplementary Fig. S2. Endoplasmic reticulum stress and unfolded protein response in normal physiology and cancer Tumor cells frequently encounter endogenous and exogenous stresses that influence protein folding in the ER, including hypoxia, inflammation, nutrient deprivation, altered glycolysis, DNA damage, genomic instability, oncogene activation, and proteasome dysfunction, can cause excessive accumulation of misfolded or unfolded proteins within the ER lumen, a condition termed "ER stress." As a response to prolonged ER stress conditions, the ER responds to the ER stress by activating intracellular signal transduction pathways, collectively referred to as the UPR, to restore-ER homeostasis (protective effect) or activate cell death (cytotoxic effect). The UPR signaling cascade comprises three parallel pathways that employ unique signal transduction mechanisms and are initiated by activating three conserved ER-stress sensors: IRE1, ATF6, and PERK. Furthermore, in mammals and under resting conditions, the critical ER-resident chaperone, GRP78/BiP, prevents the activation and blocks the downstream signaling of UPR by binding to the N-terminal side of stress sensor proteins, IRE-1, PERK, and ATF6 and maintains these sensors in an inactive state. When ER stress is triggered, and the ER luminal load of unfolded or misfolded proteins increases, the GRP78/BiP dissociates, activating IRE1, PERK, and ATF6 signaling cascades, leading to the activation of these UPR signaling pathways. Upon activation, the UPR can regulate many cellular events of tumor cells, including autophagy, ER biogenesis, cell survival, metastasis, angiogenesis, migration and invasion, chemoresistance, glycolysis, and proliferation. ER, Endoplasmic reticulum; UPR, unfolded protein response; PREK, protein kinase R (PKR) like endoplasmic reticulum kinase; ATF, activating transcription factor; IRE1, inositol requiring enzyme 1; GRP78, 78-kDa glucose-regulated protein/immunoglobulin-binding protein; CHOP, C/EBP homologous protein; AMPK, AMP-activated protein kinase; XBP-1, X-box binding protein 1; Dr5, death receptor 5; GADD34, growth arrest and DNA damage-inducible protein 34; ERO1α, ER oxidoreductin 1; GCN2, general control non-derepressible 2.