title: Molecular signal networks and regulating mechanisms of the unfolded protein response.
abstract: Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum (ER). One of the primary mechanisms is the unfolded protein response (UPR). In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein (BiP) interacts with the three sensors (protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1α (IRE1α)). Under ER stress, misfolded proteins interact with BiP, resulting in the release of BiP from the sensors. Subsequently, the three sensors dimerize and autophosphorylate to promote the signal cascades of ER stress. ER stress includes a series of positive and negative feedback signals, such as those regulating the stabilization of the sensors/BiP complex, activating and inactivating the sensors by autophosphorylation and dephosphorylation, activating specific transcription factors to enable selective transcription, and augmenting the ability to refold and export. Apart from the three basic pathways, vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR)-phospholipase C-γ (PLCγ)-mammalian target of rapamycin complex 1 (mTORC1) pathway, induced only in solid tumors, can also activate ATF6 and PERK signal cascades, and IRE1α also can be activated by activated RAC-alpha serine/threonine-protein kinase (AKT). A moderate UPR functions as a pro-survival signal to return the cell to its state of homeostasis. However, persistent ER stress will induce cells to undergo apoptosis in response to increasing reactive oxygen species (ROS), Ca2+in the cytoplasmic matrix, and other apoptosis signal cascades, such as c-Jun N-terminal kinase (JNK), signal transducer and activator of transcription 3 (STAT3), and P38, when cellular damage exceeds the capacity of this adaptive response.
authors.affiliation: Sichuan Radio and TV University, Chengdu 610073, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gong
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou 310036, China.
authors.forename: Xing-Zhi
authors.initials: XZ
authors.lastname: Wang
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou 310036, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou 310036, China.
authors.forename: Jiao-Jiao
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
authors.forename: Xiao-Yuan
authors.initials: XY
authors.lastname: Xie
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou 310036, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Hu
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou 310036, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yu
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou 310036, China.
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Liu
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou 310036, China.
authors.forename: Xing-Yan
authors.initials: XY
authors.lastname: Jiang
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou 310036, China.
authors.forename: Han-Dong
authors.initials: HD
authors.lastname: Fan
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D000072417:Protein Domains; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007136:Immunoglobulins; D046912:Multiprotein Complexes; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases
keywords: Unfolded protein response; Endoplasmic reticulum (ER) stress; Mechanism; Signal networks; Homeostasis