Abstract
Protein kinases are intracellular signaling enzymes that catalyze the phosphorylation of specific residues in their target substrate proteins. They play important role for regulation of life and death decisions. The complexity of the relationship between death receptors and protein kinases’ cell death decision-making mechanisms create many difficulties in the treatment of various diseases. The most of fifteen different cell death pathways, which are reported by Nomenclature Committee on Cell Death (NCCD) are protein kinase signal transduction-mediated negative or positive selections. Tumor necrosis factor (TNF) as a main player of death pathways is a dual-functioning molecule in that it can promote both cell survival or cell death. All apoptotic and necrotic signal transductions are conveyed through death domain-containing death receptors, which are expressed on the surface of nearly all human cells. In humans, eight members of the death receptor family have been identified. While the interaction of TNF with TNF Receptor 1 (TNFR1) activates various signal transduction pathways, different death receptors activate three main signal transduction pathways: nuclear factor kappa B (NF-ĸB)-mediated differentiation or pro-inflammatory cytokine synthesis, mitogen-activated protein kinase (MAPK)-mediated stress response and caspase-mediated apoptosis. The link between the NF-ĸB and the c-Jun NH2-terminal kinase (JNK) pathways comprise another check-point to regulate cell death. TNF-α also promotes the “receptor-interacting serine/threonine protein kinase 1” (RIPK1)/RIPK3/ mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necrosis. Thus, necrosome is mainly comprised of MLKL, RIPK3 and, in some cases, RIPK1. In fact, RIPK1 is at the crossroad between life and death, downstream of various receptors as a regulator of endoplasmic reticulum stress-induced death. TNFR1 signaling complex (TNF-RSC), which contains multiple kinase activities, promotes phosphorylation of transforming growth factor β-activated kinase 1 (TAK1), inhibitor of nuclear transcription factor κB (IκB) kinase (IKK) α/IKKβ, IκBα, and NF-κB. IKKs affect cell-survival pathways in NF-κB-independent manner. Toll-like receptor (TLR) stimulation triggers various signaling pathways dependent on myeloid differentiation factor-88 (MyD88), Interleukin-1 receptor (IL-1R)-associated kinase (IRAK1), IRAK2 and IRAK4, lead to post-translational activation of nucleotide and oligomerization domain (NLRP3). Thereby, cell fate decisions following TLR signaling is parallel with death receptor signaling. Inhibition of IKKα/IKKβ or its upstream activators sensitize cells to death by inducing RIPK1-dependent apoptosis or necroptosis. During apoptosis, several kinases of the NF-κB pathway, including IKK1 and NF-κB essential modulator (NEMO), are cleaved by cellular caspases. This event can terminate the NF-κB-derived survival signals. In both canonical and non-canonical pathways, IKK is key to NF-κB activation. Whereas, the activation process of IKK, the functions of NEMO ubiquitination, IKK-related non-canonical pathway and the nuclear transportation of NEMO and functions of IKKα are still debated in cell death. In addition, cluster of differentiation 95 (CD95)-mediated non-apoptotic signaling and CD95- death-inducing signaling complex (DISC) interactions are waiting for clarification.
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Alberola-Ila J, Hernández-Hoyos G. The Ras/MAPK cascade and the control of positive selection. Immunol Rev. 2003;191:79–96. https://doi.org/10.1034/j.1600-065x.2003.00012.x.
Alberola-Ila J, Hogquist KA, Swan KA, Bevan MJ, Perlmutter RM. Positive and negative selection invoke distinct signaling pathways. J Exp Med. 1996;184:9–18. https://doi.org/10.1084/jem.184.1.9.
Baeuerle PA, Baltimore D. NF-kappa B: ten years after. Cell. 1996;87:13–20. https://doi.org/10.1016/s0092-8674(00)81318-5.
Bagchi AK, Sharma A, Dhingra S, Lehenbauer Ludke AR, Al-Shudiefat AA-R, Singal PK. Interleukin-10 activates Toll-like receptor 4 and requires MyD88 for cardiomyocyte survival. Cytokine. 2013;61:304–14. https://doi.org/10.1016/j.cyto.2012.10.013.
Baratchian M, Davis CA, Shimizu A, Escors D, Bagnéris C, Barrett T, Collins MK. Distinct activation mechanisms of NF-κB regulator Inhibitor of NF-κB Kinase (IKK) by isoforms of the cell death regulator cellular FLICE-like Inhibitory Protein (cFLIP). J Biol Chem. 2016;291:7608–20. https://doi.org/10.1074/jbc.M116.718122.
Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183:787–91. https://doi.org/10.4049/jimmunol.0901363.
Ben-Levy R, Hooper S, Wilson R, Paterson HF, Marshall CJ. Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. Curr Biol. 1998;8:1049–57. https://doi.org/10.1016/s0960-9822(98)70442-7.
Berti DA, Seger R. The nuclear translocation of ERK. Methods Mol Biol. 2017;1487:175–94. https://doi.org/10.1007/978-1-4939-6424-6_13.
Bertrand MJM, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J, Gillard JW, Jaquith JB, Morris SJ, Barker PA. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell. 2008;30:689–700. https://doi.org/10.1016/j.molcel.2008.05.014.
Bettini ML, Kersh GJ. MAP kinase phosphatase activity sets the threshold for thymocyte positive selection. Proc Natl Acad Sci U S A. 2007;104:16257–62. https://doi.org/10.1073/pnas.0705321104.
Blackwell K, Zhang L, Thomas GS, Sun S, Nakano H, Habelhah H. TRAF2 phosphorylation modulates tumor necrosis factor alpha-induced gene expression and cell resistance to apoptosis. Mol Cell Biol. 2009;29:303–14. https://doi.org/10.1128/MCB.00699-08.
Blander JM. A long-awaited merger of the pathways mediating host defence and programmed cell death. Nat Rev Immunol. 2014;14:601–18. https://doi.org/10.1038/nri3720.
Bommhardt U, Scheuring Y, Bickel C, Zamoyska R, Hünig T. MEK activity regulates negative selection of immature CD4+CD8+ thymocytes. J Immunol. 2000;164:2326–37. https://doi.org/10.4049/jimmunol.164.5.2326.
Borghi A, Verstrepen L, Beyaert R. TRAF2 multitasking in TNF receptor-induced signaling to NF-κB, MAP kinases and cell death. Biochem Pharmacol. 2016;116:1–10. https://doi.org/10.1016/j.bcp.2016.03.009.
Bovellan M, Fritzsche M, Stevens C, Charras G. Death-associated protein kinase (DAPK) and signal transduction: blebbing in programmed cell death. FEBS J. 2010;277:58–65. https://doi.org/10.1111/j.1742-4658.2009.07412.x.
Bradley JR, Pober JS. Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene. 2001;20:6482–91. https://doi.org/10.1038/sj.onc.1204788.
Buchheit CL, Weigel KJ, Schafer ZT. Cancer cell survival during detachment from the ECM: multiple barriers to tumour progression. Nat Rev Cancer. 2014;14:632–41. https://doi.org/10.1038/nrc3789.
Buchheit CL, Angarola BL, Steiner A, Weigel KJ, Schafer ZT. Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration. Cell Death Differ. 2015;22:1275–86. https://doi.org/10.1038/cdd.2014.209.
Budhidarmo R, Day CL. The ubiquitin-associated domain of cellular inhibitor of apoptosis proteins facilitates ubiquitylation. J Biol Chem. 2014;289:25721–36. https://doi.org/10.1074/jbc.M113.545475.
Cabal-Hierro L, Rodríguez M, Artime N, Iglesias J, Ugarte L, Prado MA, Lazo PS. TRAF-mediated modulation of NF-kB AND JNK activation by TNFR2. Cell Signal. 2014;26:2658–66. https://doi.org/10.1016/j.cellsig.2014.08.011.
Caelles C, Bayod C, Morcillo M. Assaying activation and subcellular localization of ERK in cells and tissues. Methods Mol Biol. 2017;1487:89–98. https://doi.org/10.1007/978-1-4939-6424-6_6.
Chan FK-M, Luz NF, Moriwaki K. Programmed necrosis in the cross talk of cell death and inflammation. Annu Rev Immunol. 2015;33:79–106. https://doi.org/10.1146/annurev-immunol-032414-112248.
Chang L, Kamata H, Solinas G, Luo J-L, Maeda S, Venuprasad K, Liu Y-C, Karin M. The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell. 2006;124:601–13. https://doi.org/10.1016/j.cell.2006.01.021.
Chen ZJ. Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol. 2005;7:758–65. https://doi.org/10.1038/ncb0805-758.
Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science. 2002;296:1634–5. https://doi.org/10.1126/science.1071924.
Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, Ballard D, Maniatis T. Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev. 1995;9:1586–97. https://doi.org/10.1101/gad.9.13.1586.
Chen X, Li W, Ren J, Huang D, He W-T, Song Y, Yang C, Li W, Zheng X, Chen P, Han J. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Cell Res. 2014;24:105–21. https://doi.org/10.1038/cr.2013.171.
Chiribau C-B, Gaccioli F, Huang CC, Yuan CL, Hatzoglou M. Molecular symbiosis of CHOP and C/EBP beta isoform LIP contributes to endoplasmic reticulum stress-induced apoptosis. Mol Cell Biol. 2010;30:3722–31. https://doi.org/10.1128/MCB.01507-09.
Chiu Y-H, Zhao M, Chen ZJ. Ubiquitin in NF-kappaB signaling. Chem Rev. 2009;109:1549–60. https://doi.org/10.1021/cr800554j.
Cubero FJ, Singh A, Borkham-Kamphorst E, Nevzorova YA, Al Masaoudi M, Haas U, Boekschoten MV, Gassler N, Weiskirchen R, Muller M, Liedtke C, Trautwein C. TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model. Cell Death Differ. 2013;20:1580–92. https://doi.org/10.1038/cdd.2013.112.
Cullen SP, Henry CM, Kearney CJ, Logue SE, Feoktistova M, Tynan GA, Lavelle EC, Leverkus M, Martin SJ. Fas/CD95-induced chemokines can serve as “find-me” signals for apoptotic cells. Mol Cell. 2013;49:1034–48. https://doi.org/10.1016/j.molcel.2013.01.025.
Cushing L, Stochaj W, Siegel M, Czerwinski R, Dower K, Wright Q, Hirschfield M, Casanova J-L, Picard C, Puel A, Lin L-L, Rao VR. Interleukin 1/Toll-like receptor-induced autophosphorylation activates interleukin 1 receptor-associated kinase 4 and controls cytokine induction in a cell type-specific manner. J Biol Chem. 2014;289:10865–75. https://doi.org/10.1074/jbc.M113.544809.
De Smaele E, Zazzeroni F, Papa S, Nguyen DU, Jin R, Jones J, Cong R, Franzoso G. Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature. 2001;414:308–13. https://doi.org/10.1038/35104560.
Declercq W, Vanden Berghe T, Vandenabeele P. RIP kinases at the crossroads of cell death and survival. Cell. 2009;138:229–32. https://doi.org/10.1016/j.cell.2009.07.006.
Devin A, Cook A, Lin Y, Rodriguez Y, Kelliher M, Liu Z. The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation. Immunity. 2000;12:419–29. https://doi.org/10.1016/s1074-7613(00)80194-6.
Dillon CP, Oberst A, Weinlich R, Janke LJ, Kang T-B, Ben-Moshe T, Mak TW, Wallach D, Green DR. Survival function of the FADD-CASPASE-8-cFLIP(L) complex. Cell Rep. 2012;1:401–7. https://doi.org/10.1016/j.celrep.2012.03.010.
Dillon CP, Weinlich R, Rodriguez DA, Cripps JG, Quarato G, Gurung P, Verbist KC, Brewer TL, Llambi F, Gong Y-N, Janke LJ, Kelliher MA, Kanneganti T-D, Green DR. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell. 2014;157:1189–202. https://doi.org/10.1016/j.cell.2014.04.018.
Doherty FJ, Dawson S, Mayer RJ. The ubiquitin-proteasome pathway of intracellular proteolysis. Essays Biochem. 2002;38:51–63. https://doi.org/10.1042/bse0380051.
Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C, Grootjans S, Dejardin E, Vandenabeele P, Bertrand MJM. RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1/2 depletion or TAK1 kinase inhibition. Cell Death Differ. 2013;20:1381–92. https://doi.org/10.1038/cdd.2013.94.
Dondelinger Y, Jouan-Lanhouet S, Divert T, Theatre E, Bertin J, Gough PJ, Giansanti P, Heck AJR, Dejardin E, Vandenabeele P, Bertrand MJM. NF-κB-independent role of IKKα/IKKβ in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. Mol Cell. 2015;60:63–76. https://doi.org/10.1016/j.molcel.2015.07.032.
Dondelinger Y, Delanghe T, Rojas-Rivera D, Priem D, Delvaeye T, Bruggeman I, Van Herreweghe F, Vandenabeele P, Bertrand MJM. MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death. Nat Cell Biol. 2017;19:1237–47. https://doi.org/10.1038/ncb3608.
Dynek JN, Goncharov T, Dueber EC, Fedorova AV, Izrael-Tomasevic A, Phu L, Helgason E, Fairbrother WJ, Deshayes K, Kirkpatrick DS, Vucic D. c-IAP1 and UbcH5 promote K11-linked polyubiquitination of RIP1 in TNF signalling. EMBO J. 2010;29:4198–209. https://doi.org/10.1038/emboj.2010.300.
Ea C-K, Deng L, Xia Z-P, Pineda G, Chen ZJ. Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol Cell. 2006;22:245–57. https://doi.org/10.1016/j.molcel.2006.03.026.
Edlich F, Banerjee S, Suzuki M, Cleland MM, Arnoult D, Wang C, Neutzner A, Tjandra N, Youle RJ. Bcl-x(L) retrotranslocates Bax from the mitochondria into the cytosol. Cell. 2011;145:104–16. https://doi.org/10.1016/j.cell.2011.02.034.
Estornes Y, Toscano F, Virard F, Jacquemin G, Pierrot A, Vanbervliet B, Bonnin M, Lalaoui N, Mercier-Gouy P, Pachéco Y, Salaun B, Renno T, Micheau O, Lebecque S. dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8. Cell Death Differ. 2012;19:1482–94. https://doi.org/10.1038/cdd.2012.22.
Estornes Y, Aguileta MA, Dubuisson C, De Keyser J, Goossens V, Kersse K, Samali A, Vandenabeele P, Bertrand MJM. RIPK1 promotes death receptor-independent caspase-8-mediated apoptosis under unresolved ER stress conditions. Cell Death Dis. 2014;5:e1555. https://doi.org/10.1038/cddis.2014.523.
Ewings KE, Wiggins CM, Cook SJ. Bim and the pro-survival Bcl-2 proteins: opposites attract, ERK repels. Cell Cycle. 2007;6:2236–40. https://doi.org/10.4161/cc.6.18.4728.
Falschlehner C, Schaefer U, Walczak H. Following TRAIL’s path in the immune system. Immunology. 2009;127:145–54. https://doi.org/10.1111/j.1365-2567.2009.03058.x.
Fatokun AA, Dawson VL, Dawson TM. Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities. Br J Pharmacol. 2014;171:2000–16. https://doi.org/10.1111/bph.12416.
Feng S, Yang Y, Mei Y, Ma L, Zhu D, Hoti N, Castanares M, Wu M. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell Signal. 2007;19:2056–67. https://doi.org/10.1016/j.cellsig.2007.05.016.
Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, Cain K, MacFarlane M, Häcker G, Leverkus M. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol Cell. 2011;43:449–63. https://doi.org/10.1016/j.molcel.2011.06.011.
Fernandes-Alnemri T, Kang S, Anderson C, Sagara J, Fitzgerald KA, Alnemri ES. Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome. J Immunol. 2013;191:3995–9. https://doi.org/10.4049/jimmunol.1301681.
Ferrao R, Wu H. Helical assembly in the death domain (DD) superfamily. Curr Opin Struct Biol. 2012;22:241–7. https://doi.org/10.1016/j.sbi.2012.02.006.
Festjens N, Vanden Berghe T, Vandenabeele P. Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta. 2006;1757:1371–87. https://doi.org/10.1016/j.bbabio.2006.06.014.
Fornarino S, Laval G, Barreiro LB, Manry J, Vasseur E, Quintana-Murci L. Evolution of the TIR domain-containing adaptors in humans: swinging between constraint and adaptation. Mol Biol Evol. 2011;28:3087–97. https://doi.org/10.1093/molbev/msr137.
Fraczek J, Kim TW, Xiao H, Yao J, Wen Q, Li Y, Casanova J-L, Pryjma J, Li X. The kinase activity of IL-1 receptor-associated kinase 4 is required for interleukin-1 receptor/toll-like receptor-induced TAK1-dependent NFkappaB activation. J Biol Chem. 2008;283:31697–705. https://doi.org/10.1074/jbc.M804779200.
Frelin C, Imbert V, Bottero V, Gonthier N, Samraj AK, Schulze-Osthoff K, Auberger P, Courtois G, Peyron J-F. Inhibition of the NF-kappaB survival pathway via caspase-dependent cleavage of the IKK complex scaffold protein and NF-kappaB essential modulator NEMO. Cell Death Differ. 2008;15:152–60. https://doi.org/10.1038/sj.cdd.4402240.
Fricker N, Beaudouin J, Richter P, Eils R, Krammer PH, Lavrik IN. Model-based dissection of CD95 signaling dynamics reveals both a pro- and antiapoptotic role of c-FLIPL. J Cell Biol. 2010;190:377–89. https://doi.org/10.1083/jcb.201002060.
Fujita H, Rahighi S, Akita M, Kato R, Sasaki Y, Wakatsuki S, Iwai K. Mechanism underlying IκB kinase activation mediated by the linear ubiquitin chain assembly complex. Mol Cell Biol. 2014;34:1322–35. https://doi.org/10.1128/MCB.01538-13.
Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, Gottlieb E, Green DR, Hengartner MO, Kepp O, Knight RA, Kumar S, Lipton SA, Lu X, Madeo F, Malorni W, Mehlen P, Nuñez G, Peter ME, Piacentini M, Rubinsztein DC, Shi Y, Simon H-U, Vandenabeele P, White E, Yuan J, Zhivotovsky B, Melino G, Kroemer G. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012;19:107–20. https://doi.org/10.1038/cdd.2011.96.
Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M, Antonov AV, Arama E, Baehrecke EH, Barlev NA, Bazan NG, Bernassola F, Bertrand MJM, Bianchi K, Blagosklonny MV, Blomgren K, Borner C, Boya P, Brenner C, Campanella M, Candi E, Carmona-Gutierrez D, Cecconi F, Chan FK-M, Chandel NS, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Cohen GM, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D’Angiolella V, Dawson TM, Dawson VL, De Laurenzi V, De Maria R, Debatin K-M, DeBerardinis RJ, Deshmukh M, Di Daniele N, Di Virgilio F, Dixit VM, Dixon SJ, Duckett CS, Dynlacht BD, El-Deiry WS, Elrod JW, Fimia GM, Fulda S, García-Sáez AJ, Garg AD, Garrido C, Gavathiotis E, Golstein P, Gottlieb E, Green DR, Greene LA, Gronemeyer H, Gross A, Hajnoczky G, Hardwick JM, Harris IS, Hengartner MO, Hetz C, Ichijo H, Jäättelä M, Joseph B, Jost PJ, Juin PP, Kaiser WJ, Karin M, Kaufmann T, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Knight RA, Kumar S, Lee SW, Lemasters JJ, Levine B, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Lowe SW, Luedde T, Lugli E, MacFarlane M, Madeo F, Malewicz M, Malorni W, Manic G, Marine J-C, Martin SJ, Martinou J-C, Medema JP, Mehlen P, Meier P, Melino S, Miao EA, Molkentin JD, Moll UM, Muñoz-Pinedo C, Nagata S, Nuñez G, Oberst A, Oren M, Overholtzer M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pereira DM, Pervaiz S, Peter ME, Piacentini M, Pinton P, Prehn JHM, Puthalakath H, Rabinovich GA, Rehm M, Rizzuto R, Rodrigues CMP, Rubinsztein DC, Rudel T, Ryan KM, Sayan E, Scorrano L, Shao F, Shi Y, Silke J, Simon H-U, Sistigu A, Stockwell BR, Strasser A, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Thorburn A, Tsujimoto Y, Turk B, Vanden Berghe T, Vandenabeele P, Vander Heiden MG, Villunger A, Virgin HW, Vousden KH, Vucic D, Wagner EF, Walczak H, Wallach D, Wang Y, Wells JA, Wood W, Yuan J, Zakeri Z, Zhivotovsky B, Zitvogel L, Melino G, Kroemer G. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25:486–541. https://doi.org/10.1038/s41418-017-0012-4.
Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, Webb AI, Rickard JA, Anderton H, Wong WW-L, Nachbur U, Gangoda L, Warnken U, Purcell AW, Silke J, Walczak H. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature. 2011;471:591–6. https://doi.org/10.1038/nature09816.
Geserick P, Hupe M, Moulin M, Wong WW-L, Feoktistova M, Kellert B, Gollnick H, Silke J, Leverkus M. Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment. J Cell Biol. 2009;187:1037–54. https://doi.org/10.1083/jcb.200904158.
Gibert B, Mehlen P. Dependence receptors and cancer: addiction to trophic ligands. Cancer Res. 2015;75:5171–5. https://doi.org/10.1158/0008-5472.CAN-14-3652.
Golstein P, Kroemer G. Redundant cell death mechanisms as relics and backups. Cell Death Differ. 2005;12(Suppl 2):1490–6. https://doi.org/10.1038/sj.cdd.4401607.
Golstein P, Kroemer G. Cell death by necrosis: towards a molecular definition. Trends Biochem Sci. 2007;32:37–43. https://doi.org/10.1016/j.tibs.2006.11.001.
Gómez-Angelats M, Cidlowski JA. Protein kinase C regulates FADD recruitment and death-inducing signaling complex formation in Fas/CD95-induced apoptosis. J Biol Chem. 2001;276:44944–52. https://doi.org/10.1074/jbc.M104919200.
Guo X, Yin H, Chen Y, Li L, Li J, Liu Q. TAK1 regulates caspase 8 activation and necroptotic signaling via multiple cell death checkpoints. Cell Death Dis. 2016;7:e2381. https://doi.org/10.1038/cddis.2016.294.
Gyrd-Hansen M, Meier P. IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat Rev Cancer. 2010;10:561–74. https://doi.org/10.1038/nrc2889.
Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E, Feltham R, Vince J, Warnken U, Wenger T, Koschny R, Komander D, Silke J, Walczak H. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell. 2009;36:831–44. https://doi.org/10.1016/j.molcel.2009.10.013.
Häcker H, Karin M. Regulation and function of IKK and IKK-related kinases. Sci STKE. 2006;2006:re13. https://doi.org/10.1126/stke.3572006re13.
Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6:1099–108. https://doi.org/10.1016/s1097-2765(00)00108-8.
He JQ, Saha SK, Kang JR, Zarnegar B, Cheng G. Specificity of TRAF3 in its negative regulation of the noncanonical NF-kappa B pathway. J Biol Chem. 2007;282:3688–94. https://doi.org/10.1074/jbc.M610271200.
Hetz C, Chevet E, Oakes SA. Proteostasis control by the unfolded protein response. Nat Cell Biol. 2015;17:829–38. https://doi.org/10.1038/ncb3184.
Hildebrand JM, Tanzer MC, Lucet IS, Young SN, Spall SK, Sharma P, Pierotti C, Garnier J-M, Dobson RCJ, Webb AI, Tripaydonis A, Babon JJ, Mulcair MD, Scanlon MJ, Alexander WS, Wilks AF, Czabotar PE, Lessene G, Murphy JM, Silke J. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc Natl Acad Sci U S A. 2014;111:15072–7. https://doi.org/10.1073/pnas.1408987111.
Hinz M, Scheidereit C. The IκB kinase complex in NF-κB regulation and beyond. EMBO Rep. 2014;15:46–61. https://doi.org/10.1002/embr.201337983.
Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2000;1:489–95. https://doi.org/10.1038/82732.
Hong S-K, Wu P-K, Park J-I. A cellular threshold for active ERK1/2 levels determines Raf/MEK/ERK-mediated growth arrest versus death responses. Cell Signal. 2018;42:11–20. https://doi.org/10.1016/j.cellsig.2017.10.001.
Höpker K, Hagmann H, Khurshid S, Chen S, Schermer B, Benzing T, Reinhardt HC. Putting the brakes on p53-driven apoptosis. Cell Cycle. 2012;11:4122–8. https://doi.org/10.4161/cc.21997.
Horn S, Hughes MA, Schilling R, Sticht C, Tenev T, Ploesser M, Meier P, Sprick MR, MacFarlane M, Leverkus M. Caspase-10 negatively regulates Caspase-8-mediated cell death, switching the response to CD95L in favor of NF-κB activation and cell survival. Cell Rep. 2017;19:785–97. https://doi.org/10.1016/j.celrep.2017.04.010.
Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol. 2006;26:3071–84. https://doi.org/10.1128/MCB.26.8.3071-3084.2006.
Hu H, Brittain GC, Chang J-H, Puebla-Osorio N, Jin J, Zal A, Xiao Y, Cheng X, Chang M, Fu Y-X, Zal T, Zhu C, Sun S-C. OTUD7B controls non-canonical NF-κB activation through deubiquitination of TRAF3. Nature. 2013;494:371–4. https://doi.org/10.1038/nature11831.
Ikeda F, Deribe YL, Skånland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk SJL, Goswami P, Nagy V, Terzic J, Tokunaga F, Androulidaki A, Nakagawa T, Pasparakis M, Iwai K, Sundberg JP, Schaefer L, Rittinger K, Macek B, Dikic I. SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature. 2011;471:637–41. https://doi.org/10.1038/nature09814.
Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schröter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J. Inhibition of death receptor signals by cellular FLIP. Nature. 1997;388:190–5. https://doi.org/10.1038/40657.
Iwai K. Diverse roles of the ubiquitin system in NF-κB activation. Biochim Biophys Acta. 2014;1843:129–36. https://doi.org/10.1016/j.bbamcr.2013.03.011.
Jaco I, Annibaldi A, Lalaoui N, Wilson R, Tenev T, Laurien L, Kim C, Jamal K, Wicky John S, Liccardi G, Chau D, Murphy JM, Brumatti G, Feltham R, Pasparakis M, Silke J, Meier P. MK2 phosphorylates RIPK1 to prevent TNF-induced cell death. Mol Cell. 2017;66:698–710.e5. https://doi.org/10.1016/j.molcel.2017.05.003.
Joo D, Tang Y, Blonska M, Jin J, Zhao X, Lin X. Regulation of linear ubiquitin chain assembly complex by caspase-mediated cleavage of RNF31. Mol Cell Biol. 2016;36:3010–8. https://doi.org/10.1128/MCB.00474-16.
Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem. 2012;287:36617–22. https://doi.org/10.1074/jbc.M112.407130.
Kaiser WJ, Offermann MK. Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif. J Immunol. 2005;174:4942–52. https://doi.org/10.4049/jimmunol.174.8.4942.
Kaiser WJ, Sridharan H, Huang C, Mandal P, Upton JW, Gough PJ, Sehon CA, Marquis RW, Bertin J, Mocarski ES. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J Biol Chem. 2013;288:31268–79. https://doi.org/10.1074/jbc.M113.462341.
Kang S, Fernandes-Alnemri T, Rogers C, Mayes L, Wang Y, Dillon C, Roback L, Kaiser W, Oberst A, Sagara J, Fitzgerald KA, Green DR, Zhang J, Mocarski ES, Alnemri ES. Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3. Nat Commun. 2015;6:7515. https://doi.org/10.1038/ncomms8515.
Kavuri SM, Geserick P, Berg D, Dimitrova DP, Feoktistova M, Siegmund D, Gollnick H, Neumann M, Wajant H, Leverkus M. Cellular FLICE-inhibitory protein (cFLIP) isoforms block CD95- and TRAIL death receptor-induced gene induction irrespective of processing of caspase-8 or cFLIP in the death-inducing signaling complex. J Biol Chem. 2011;286:16631–46. https://doi.org/10.1074/jbc.M110.148585.
Kawagoe T, Sato S, Matsushita K, Kato H, Matsui K, Kumagai Y, Saitoh T, Kawai T, Takeuchi O, Akira S. Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat Immunol. 2008;9:684–91. https://doi.org/10.1038/ni.1606.
Khan N, Lawlor KE, Murphy JM, Vince JE. More to life than death: molecular determinants of necroptotic and non-necroptotic RIP3 kinase signaling. Curr Opin Immunol. 2014;26:76–89. https://doi.org/10.1016/j.coi.2013.10.017.
Kim Y-Y, Park B-J, Seo G-J, Lim J-Y, Lee S-M, Kimm K-C, Park C, Kim J, Park SI. Long form of cellular FLICE-inhibitory protein interacts with Daxx and prevents Fas-induced JNK activation. Biochem Biophys Res Commun. 2003;312:426–33. https://doi.org/10.1016/j.bbrc.2003.10.144.
Kim H, Tu H-C, Ren D, Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJ-D, Cheng EH-Y. Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol Cell. 2009a;36:487–99. https://doi.org/10.1016/j.molcel.2009.09.030.
Kim I, Shu C-W, Xu W, Shiau C-W, Grant D, Vasile S, Cosford NDP, Reed JC. Chemical biology investigation of cell death pathways activated by endoplasmic reticulum stress reveals cytoprotective modulators of ASK1. J Biol Chem. 2009b;284:1593–603. https://doi.org/10.1074/jbc.M807308200.
Kirisako T, Kamei K, Murata S, Kato M, Fukumoto H, Kanie M, Sano S, Tokunaga F, Tanaka K, Iwai K. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J. 2006;25:4877–87. https://doi.org/10.1038/sj.emboj.7601360.
Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A. Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity. 2000;12:611–20. https://doi.org/10.1016/s1074-7613(00)80212-5.
Kondylis V, Kumari S, Vlantis K, Pasparakis M. The interplay of IKK, NF-κB and RIPK1 signaling in the regulation of cell death, tissue homeostasis and inflammation. Immunol Rev. 2017;277:113–27. https://doi.org/10.1111/imr.12550.
Kovalenko A, Wallach D. If the prophet does not come to the mountain: dynamics of signaling complexes in NF-kappaB activation. Mol Cell. 2006;22:433–6. https://doi.org/10.1016/j.molcel.2006.05.002.
Krappmann D, Scheidereit C. A pervasive role of ubiquitin conjugation in activation and termination of IkappaB kinase pathways. EMBO Rep. 2005;6:321–6. https://doi.org/10.1038/sj.embor.7400380.
Kreuz S, Siegmund D, Scheurich P, Wajant H. NF-kappaB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling. Mol Cell Biol. 2001;21:3964–73. https://doi.org/10.1128/MCB.21.12.3964-3973.2001.
Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G, Nomenclature Committee on Cell Death 2009. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 2009;16:3–11. https://doi.org/10.1038/cdd.2008.150.
Kruiswijk F, Labuschagne CF, Vousden KH. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol. 2015;16:393–405. https://doi.org/10.1038/nrm4007.
Kuriakose T, Man SM, Malireddi RKS, Karki R, Kesavardhana S, Place DE, Neale G, Vogel P, Kanneganti T-D. ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways. Sci Immunol. 2016;1 https://doi.org/10.1126/sciimmunol.aag2045.
Kurokawa M, Kornbluth S. Caspases and kinases in a death grip. Cell. 2009;138:838–54. https://doi.org/10.1016/j.cell.2009.08.021.
Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, Newmeyer DD. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell. 2005;17:525–35. https://doi.org/10.1016/j.molcel.2005.02.003.
Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev. 2001;81:807–69. https://doi.org/10.1152/physrev.2001.81.2.807.
Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol Rev. 2012;92:689–737. https://doi.org/10.1152/physrev.00028.2011.
Lafont E, Kantari-Mimoun C, Draber P, De Miguel D, Hartwig T, Reichert M, Kupka S, Shimizu Y, Taraborrelli L, Spit M, Sprick MR, Walczak H. The linear ubiquitin chain assembly complex regulates TRAIL-induced gene activation and cell death. EMBO J. 2017;36:1147–66. https://doi.org/10.15252/embj.201695699.
Laplantine E, Fontan E, Chiaravalli J, Lopez T, Lakisic G, Véron M, Agou F, Israël A. NEMO specifically recognizes K63-linked poly-ubiquitin chains through a new bipartite ubiquitin-binding domain. EMBO J. 2009;28:2885–95. https://doi.org/10.1038/emboj.2009.241.
Lavrik IN, Krammer PH. Regulation of CD95/Fas signaling at the DISC. Cell Death Differ. 2012;19:36–41. https://doi.org/10.1038/cdd.2011.155.
Le Gallo M, Poissonnier A, Blanco P, Legembre P. CD95/Fas, non-apoptotic signaling pathways, and kinases. Front Immunol. 2017;8:1216. https://doi.org/10.3389/fimmu.2017.01216.
Legarda-Addison D, Hase H, O’Donnell MA, Ting AT. NEMO/IKKgamma regulates an early NF-kappaB-independent cell-death checkpoint during TNF signaling. Cell Death Differ. 2009;16:1279–88. https://doi.org/10.1038/cdd.2009.41.
Levkau B, Scatena M, Giachelli CM, Ross R, Raines EW. Apoptosis overrides survival signals through a caspase-mediated dominant-negative NF-kappa B loop. Nat Cell Biol. 1999;1:227–33. https://doi.org/10.1038/12050.
Ley R, Hadfield K, Howes E, Cook SJ. Identification of a DEF-type docking domain for extracellular signal-regulated kinases 1/2 that directs phosphorylation and turnover of the BH3-only protein BimEL. J Biol Chem. 2005;280:17657–63. https://doi.org/10.1074/jbc.M412342200.
Li H, Kobayashi M, Blonska M, You Y, Lin X. Ubiquitination of RIP is required for tumor necrosis factor alpha-induced NF-kappaB activation. J Biol Chem. 2006;281:13636–43. https://doi.org/10.1074/jbc.M600620200.
Li L, Chen Y, Doan J, Murray J, Molkentin JD, Liu Q. Transforming growth factor β-activated kinase 1 signaling pathway critically regulates myocardial survival and remodeling. Circulation. 2014;130:2162–72. https://doi.org/10.1161/CIRCULATIONAHA.114.011195.
Liao G, Zhang M, Harhaj EW, Sun S-C. Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J Biol Chem. 2004;279:26243–50. https://doi.org/10.1074/jbc.M403286200.
Lin Y, Devin A, Rodriguez Y, Liu ZG. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 1999;13:2514–26. https://doi.org/10.1101/gad.13.19.2514.
Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, Shokat KM, Lavail MM, Walter P. IRE1 signaling affects cell fate during the unfolded protein response. Science. 2007;318:944–9. https://doi.org/10.1126/science.1146361.
Liu F, Xia Y, Parker AS, Verma IM. IKK biology. Immunol Rev. 2012;246:239–53. https://doi.org/10.1111/j.1600-065X.2012.01107.x.
Luna-Vargas MPA, Chipuk JE. Physiological and pharmacological control of BAK, BAX, and beyond. Trends Cell Biol. 2016;26:906–17. https://doi.org/10.1016/j.tcb.2016.07.002.
Mahoney DJ, Cheung HH, Mrad RL, Plenchette S, Simard C, Enwere E, Arora V, Mak TW, Lacasse EC, Waring J, Korneluk RG. Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation. Proc Natl Acad Sci U S A. 2008;105:11778–83. https://doi.org/10.1073/pnas.0711122105.
Manke IA, Nguyen A, Lim D, Stewart MQ, Elia AEH, Yaffe MB. MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. Mol Cell. 2005;17:37–48. https://doi.org/10.1016/j.molcel.2004.11.021.
Mariathasan S, Zakarian A, Bouchard D, Michie AM, Zúñiga-Pflücker JC, Ohashi PS. Duration and strength of extracellular signal-regulated kinase signals are altered during positive versus negative thymocyte selection. J Immunol. 2001;167:4966–73. https://doi.org/10.4049/jimmunol.167.9.4966.
Matsuzawa A, Nishitoh H, Tobiume K, Takeda K, Ichijo H. Physiological roles of ASK1-mediated signal transduction in oxidative stress- and endoplasmic reticulum stress-induced apoptosis: advanced findings from ASK1 knockout mice. Antioxid Redox Signal. 2002;4:415–25. https://doi.org/10.1089/15230860260196218.
Mebratu Y, Tesfaigzi Y. How ERK1/2 activation controls cell proliferation and cell death: is subcellular localization the answer? Cell Cycle. 2009;8:1168–75. https://doi.org/10.4161/cc.8.8.8147.
Mehlen P, Thibert C. Dependence receptors: between life and death. Cell Mol Life Sci. 2004;61:1854–66. https://doi.org/10.1007/s00018-004-3467-7.
Menon MB, Gropengießer J, Fischer J, Novikova L, Deuretzbacher A, Lafera J, Schimmeck H, Czymmeck N, Ronkina N, Kotlyarov A, Aepfelbacher M, Gaestel M, Ruckdeschel K. p38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection. Nat Cell Biol. 2017;19:1248–59. https://doi.org/10.1038/ncb3614.
Metzger MB, Pruneda JN, Klevit RE, Weissman AM. RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination. Biochim Biophys Acta. 2014;1843:47–60. https://doi.org/10.1016/j.bbamcr.2013.05.026.
Meylan E, Tschopp J. The RIP kinases: crucial integrators of cellular stress. Trends Biochem Sci. 2005;30:151–9. https://doi.org/10.1016/j.tibs.2005.01.003.
Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114:181–90. https://doi.org/10.1016/s0092-8674(03)00521-x.
Micheau O, Lens S, Gaide O, Alevizopoulos K, Tschopp J. NF-kappaB signals induce the expression of c-FLIP. Mol Cell Biol. 2001;21:5299–305. https://doi.org/10.1128/MCB.21.16.5299-5305.2001.
Middleton AJ, Budhidarmo R, Das A, Zhu J, Foglizzo M, Mace PD, Day CL. The activity of TRAF RING homo- and heterodimers is regulated by zinc finger 1. Nat Commun. 2017;8:1788. https://doi.org/10.1038/s41467-017-01665-3.
Mohideen F, Paulo JA, Ordureau A, Gygi SP, Harper JW. Quantitative Phospho-proteomic analysis of TNFα/NFκB signaling reveals a role for RIPK1 phosphorylation in suppressing necrotic cell death. Mol Cell Proteomics. 2017;16:1200–16. https://doi.org/10.1074/mcp.M117.068189.
Muppidi JR, Tschopp J, Siegel RM. Life and death decisions: secondary complexes and lipid rafts in TNF receptor family signal transduction. Immunity. 2004;21:461–5. https://doi.org/10.1016/j.immuni.2004.10.001.
Murphy JM, Czabotar PE, Hildebrand JM, Lucet IS, Zhang J-G, Alvarez-Diaz S, Lewis R, Lalaoui N, Metcalf D, Webb AI, Young SN, Varghese LN, Tannahill GM, Hatchell EC, Majewski IJ, Okamoto T, Dobson RCJ, Hilton DJ, Babon JJ, Nicola NA, Strasser A, Silke J, Alexander WS. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity. 2013;39:443–53. https://doi.org/10.1016/j.immuni.2013.06.018.
Nakajima A, Komazawa-Sakon S, Takekawa M, Sasazuki T, Yeh W-C, Yagita H, Okumura K, Nakano H. An antiapoptotic protein, c-FLIPL, directly binds to MKK7 and inhibits the JNK pathway. EMBO J. 2006;25:5549–59. https://doi.org/10.1038/sj.emboj.7601423.
Nakamura A, Kimura H. A new role of GCN2 in the nucleolus. Biochem Biophys Res Commun. 2017;485:484–91. https://doi.org/10.1016/j.bbrc.2017.02.038.
Nyarko A, Barbar E. Light chain-dependent self-association of dynein intermediate chain. J Biol Chem. 2011;286:1556–66. https://doi.org/10.1074/jbc.M110.171686.
O’Donnell MA, Legarda-Addison D, Skountzos P, Yeh WC, Ting AT. Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling. Curr Biol. 2007;17:418–24. https://doi.org/10.1016/j.cub.2007.01.027.
O’Donnell MA, Hase H, Legarda D, Ting AT. NEMO inhibits programmed necrosis in an NFκB-independent manner by restraining RIP1. PLoS One. 2012;7:e41238. https://doi.org/10.1371/journal.pone.0041238.
O’Neill LAJ, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol. 2007;7:353–64. https://doi.org/10.1038/nri2079.
O’Shea CC, Crompton T, Rosewell IR, Hayday AC, Owen MJ. Raf regulates positive selection. Eur J Immunol. 1996;26:2350–5. https://doi.org/10.1002/eji.1830261012.
Oberst A. MK2 balances inflammation and cell death. Nat Cell Biol. 2017;19:1150–2. https://doi.org/10.1038/ncb3619.
Oberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P, Pop C, Hakem R, Salvesen GS, Green DR. Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature. 2011;471:363–7. https://doi.org/10.1038/nature09852.
Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. 2009;1:a000034. https://doi.org/10.1101/cshperspect.a000034.
Pal HC, Sehar I, Bhushan S, Gupta BD, Saxena AK. Activation of caspases and poly (ADP-ribose) polymerase cleavage to induce apoptosis in leukemia HL-60 cells by Inula racemosa. Toxicol In Vitro. 2010;24:1599–609. https://doi.org/10.1016/j.tiv.2010.06.007.
Paoli P, Giannoni E, Chiarugi P. Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta. 2013;1833:3481–98. https://doi.org/10.1016/j.bbamcr.2013.06.026.
Park YC, Ye H, Hsia C, Segal D, Rich RL, Liou HC, Myszka DG, Wu H. A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction. Cell. 2000;101:777–87. https://doi.org/10.1016/s0092-8674(00)80889-2.
Pasparakis M, Vandenabeele P. Necroptosis and its role in inflammation. Nature. 2015;517:311–20. https://doi.org/10.1038/nature14191.
Pihán P, Carreras-Sureda A, Hetz C. BCL-2 family: integrating stress responses at the ER to control cell demise. Cell Death Differ. 2017;24:1478–87. https://doi.org/10.1038/cdd.2017.82.
Pomerantz JL, Baltimore D. Two pathways to NF-kappaB. Mol Cell. 2002;10:693–5. https://doi.org/10.1016/s1097-2765(02)00697-4.
Puthalakath H, Huang DC, O’Reilly LA, King SM, Strasser A. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell. 1999;3:287–96. https://doi.org/10.1016/s1097-2765(00)80456-6.
Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, Strasser A. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell. 2007;129:1337–49. https://doi.org/10.1016/j.cell.2007.04.027.
Qin J, Yao J, Cui G, Xiao H, Kim TW, Fraczek J, Wightman P, Sato S, Akira S, Puel A, Casanova J-L, Su B, Li X. TLR8-mediated NF-kappaB and JNK activation are TAK1-independent and MEKK3-dependent. J Biol Chem. 2006;281:21013–21. https://doi.org/10.1074/jbc.M512908200.
Rahighi S, Ikeda F, Kawasaki M, Akutsu M, Suzuki N, Kato R, Kensche T, Uejima T, Bloor S, Komander D, Randow F, Wakatsuki S, Dikic I. Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell. 2009;136:1098–109. https://doi.org/10.1016/j.cell.2009.03.007.
Rayavarapu RR, Heiden B, Pagani N, Shaw MM, Shuff S, Zhang S, Schafer ZT. The role of multicellular aggregation in the survival of ErbB2-positive breast cancer cells during extracellular matrix detachment. J Biol Chem. 2015;290:8722–33. https://doi.org/10.1074/jbc.M114.612754.
Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB. p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell. 2007;11:175–89. https://doi.org/10.1016/j.ccr.2006.11.024.
Remouchamps C, Dejardin E. Methods to assess the activation of the alternative (noncanonical) NF-κB pathway by non-death TNF receptors. Methods Mol Biol. 2015;1280:103–19. https://doi.org/10.1007/978-1-4939-2422-6_7.
Ren D, Tu H-C, Kim H, Wang GX, Bean GR, Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJ-D, Cheng EH-Y. BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science. 2010;330:1390–3. https://doi.org/10.1126/science.1190217.
Rodriguez DA, Weinlich R, Brown S, Guy C, Fitzgerald P, Dillon CP, Oberst A, Quarato G, Low J, Cripps JG, Chen T, Green DR. Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis. Cell Death Differ. 2016;23:76–88. https://doi.org/10.1038/cdd.2015.70.
Ronkina N, Kotlyarov A, Gaestel M. MK2 and MK3--a pair of isoenzymes? Front Biosci. 2008;13:5511–21. https://doi.org/10.2741/3095.
Roskoski R. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res. 2012;66:105–43. https://doi.org/10.1016/j.phrs.2012.04.005.
Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell. 1995;83:1243–52. https://doi.org/10.1016/0092-8674(95)90149-3.
Samanta AK, Huang HJ, Le X-F, Mao W, Lu KH, Bast RC, Liao WS-L. MEKK3 expression correlates with nuclear factor kappa B activity and with expression of antiapoptotic genes in serous ovarian carcinoma. Cancer. 2009;115:3897–908. https://doi.org/10.1002/cncr.24445.
Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, Akira S. Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol. 2003;171:4304–10. https://doi.org/10.4049/jimmunol.171.8.4304.
Scheidereit C. IkappaB kinase complexes: gateways to NF-kappaB activation and transcription. Oncogene. 2006;25:6685–705. https://doi.org/10.1038/sj.onc.1209934.
Sessler T, Healy S, Samali A, Szegezdi E. Structural determinants of DISC function: new insights into death receptor-mediated apoptosis signalling. Pharmacol Ther. 2013;140:186–99. https://doi.org/10.1016/j.pharmthera.2013.06.009.
Shin S, Buel GR, Wolgamott L, Plas DR, Asara JM, Blenis J, Yoon S-O. ERK2 mediates metabolic stress response to regulate cell fate. Mol Cell. 2015;59:382–98. https://doi.org/10.1016/j.molcel.2015.06.020.
Siegmund D, Lang I, Wajant H. Cell death-independent activities of the death receptors CD95, TRAILR1, and TRAILR2. FEBS J. 2017;284:1131–59. https://doi.org/10.1111/febs.13968.
Silke J. The regulation of TNF signalling: what a tangled web we weave. Curr Opin Immunol. 2011;23:620–6. https://doi.org/10.1016/j.coi.2011.08.002.
Skaug B, Jiang X, Chen ZJ. The role of ubiquitin in NF-kappaB regulatory pathways. Annu Rev Biochem. 2009;78:769–96. https://doi.org/10.1146/annurev.biochem.78.070907.102750.
Stanger BZ, Leder P, Lee TH, Kim E, Seed B. RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death. Cell. 1995;81:513–23. https://doi.org/10.1016/0092-8674(95)90072-1.
Su B, Karin M. Mitogen-activated protein kinase cascades and regulation of gene expression. Curr Opin Immunol. 1996;8:402–11. https://doi.org/10.1016/s0952-7915(96)80131-2.
Sun S-C. Non-canonical NF-κB signaling pathway. Cell Res. 2011;21:71–85. https://doi.org/10.1038/cr.2010.177.
Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X, Wang X. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012a;148:213–27. https://doi.org/10.1016/j.cell.2011.11.031.
Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X, Wang X. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012b;148:213–27. https://doi.org/10.1016/j.cell.2011.11.031.
Sun B, Ding R, Yu W, Wu Y, Wang B, Li Q. Advanced oxidative protein products induced human keratinocyte apoptosis through the NOX-MAPK pathway. Apoptosis. 2016;21:825–35. https://doi.org/10.1007/s10495-016-1245-2.
Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011;13:184–90. https://doi.org/10.1038/ncb0311-184.
Tait SWG, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 2010;11:621–32. https://doi.org/10.1038/nrm2952.
Takada Y, Singh S, Aggarwal BB. Identification of a p65 peptide that selectively inhibits NF-kappa B activation induced by various inflammatory stimuli and its role in down-regulation of NF-kappaB-mediated gene expression and up-regulation of apoptosis. J Biol Chem. 2004;279:15096–104. https://doi.org/10.1074/jbc.M311192200.
Takeda K, Akira S. TLR signaling pathways. Semin Immunol. 2004;16:3–9. https://doi.org/10.1016/j.smim.2003.10.003.
Takiuchi T, Nakagawa T, Tamiya H, Fujita H, Sasaki Y, Saeki Y, Takeda H, Sawasaki T, Buchberger A, Kimura T, Iwai K. Suppression of LUBAC-mediated linear ubiquitination by a specific interaction between LUBAC and the deubiquitinases CYLD and OTULIN. Genes Cells. 2014;19:254–72. https://doi.org/10.1111/gtc.12128.
Tenev T, Bianchi K, Darding M, Broemer M, Langlais C, Wallberg F, Zachariou A, Lopez J, MacFarlane M, Cain K, Meier P. The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol Cell. 2011;43:432–48. https://doi.org/10.1016/j.molcel.2011.06.006.
Thibert C, Fombonne J. Dependence receptors: mechanisms of an announced death. Cell Cycle. 2010;9:2085–91. https://doi.org/10.4161/cc.9.11.11809.
Ting AT, Bertrand MJM. More to life than NF-κB in TNFR1 signaling. Trends Immunol. 2016;37:535–45. https://doi.org/10.1016/j.it.2016.06.002.
Ting JP-Y, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, Flavell RA, Girardin SE, Godzik A, Harton JA, Hoffman HM, Hugot J-P, Inohara N, Mackenzie A, Maltais LJ, Nunez G, Ogura Y, Otten LA, Philpott D, Reed JC, Reith W, Schreiber S, Steimle V, Ward PA. The NLR gene family: a standard nomenclature. Immunity. 2008;28:285–7. https://doi.org/10.1016/j.immuni.2008.02.005.
Tokunaga F. Linear ubiquitination-mediated NF-κB regulation and its related disorders. J Biochem. 2013;154:313–23. https://doi.org/10.1093/jb/mvt079.
Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, Nakagawa T, Kato M, Murata S, Yamaoka S, Yamamoto M, Akira S, Takao T, Tanaka K, Iwai K. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol. 2009;11:123–32. https://doi.org/10.1038/ncb1821.
Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M, Sakata S, Tanaka K, Nakano H, Iwai K. SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature. 2011;471:633–6. https://doi.org/10.1038/nature09815.
Tsuchiya Y, Nakabayashi O, Nakano H. FLIP the switch: regulation of apoptosis and necroptosis by cFLIP. Int J Mol Sci. 2015;16:30321–41. https://doi.org/10.3390/ijms161226232.
Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000;287:664–6. https://doi.org/10.1126/science.287.5453.664.
Vajjhala PR, Mirams RE, Hill JM. Multiple binding sites on the pyrin domain of ASC protein allow self-association and interaction with NLRP3 protein. J Biol Chem. 2012;287:41732–43. https://doi.org/10.1074/jbc.M112.381228.
Vallabhapurapu S, Matsuzawa A, Zhang W, Tseng P-H, Keats JJ, Wang H, Vignali DAA, Bergsagel PL, Karin M. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nat Immunol. 2008;9:1364–70. https://doi.org/10.1038/ni.1678.
Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol. 2014;15:135–47. https://doi.org/10.1038/nrm3737.
Vanden Berghe T, Hassannia B, Vandenabeele P. An outline of necrosome triggers. Cell Mol Life Sci. 2016;73:2137–52. https://doi.org/10.1007/s00018-016-2189-y.
Vandenabeele P, Declercq W, Van Herreweghe F, Vanden Berghe T. The role of the kinases RIP1 and RIP3 in TNF-induced necrosis. Sci Signal. 2010;3:re4. https://doi.org/10.1126/scisignal.3115re4.
Varfolomeev EE, Ashkenazi A. Tumor necrosis factor: an apoptosis JuNKie? Cell. 2004;116:491–7. https://doi.org/10.1016/s0092-8674(04)00166-7.
Varfolomeev E, Vucic D. (Un)expected roles of c-IAPs in apoptotic and NFkappaB signaling pathways. Cell Cycle. 2008;7:1511–21. https://doi.org/10.4161/cc.7.11.5959.
Varfolomeev E, Maecker H, Sharp D, Lawrence D, Renz M, Vucic D, Ashkenazi A. Molecular determinants of kinase pathway activation by Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand. J Biol Chem. 2005;280:40599–608. https://doi.org/10.1074/jbc.M509560200.
Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, Zobel K, Dynek JN, Elliott LO, Wallweber HJA, Flygare JA, Fairbrother WJ, Deshayes K, Dixit VM, Vucic D. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell. 2007;131:669–81. https://doi.org/10.1016/j.cell.2007.10.030.
Varfolomeev E, Goncharov T, Maecker H, Zobel K, Kömüves LG, Deshayes K, Vucic D. Cellular inhibitors of apoptosis are global regulators of NF-κB and MAPK activation by members of the TNF family of receptors. Sci Signal. 2012;5:ra22. https://doi.org/10.1126/scisignal.2001878.
Vaux DL, Silke J. IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol. 2005;6:287–97. https://doi.org/10.1038/nrm1621.
Vessoni AT, Filippi-Chiela EC, Menck CF, Lenz G. Autophagy and genomic integrity. Cell Death Differ. 2013;20:1444–54. https://doi.org/10.1038/cdd.2013.103.
Virág L, Robaszkiewicz A, Rodriguez-Vargas JM, Oliver FJ. Poly(ADP-ribose) signaling in cell death. Mol Asp Med. 2013;34:1153–67. https://doi.org/10.1016/j.mam.2013.01.007.
Vitale I, Manic G, De Maria R, Kroemer G, Galluzzi L. DNA Damage in Stem Cells. Mol Cell. 2017;66:306–19. https://doi.org/10.1016/j.molcel.2017.04.006.
Wajant H. The Fas signaling pathway: more than a paradigm. Science. 2002;296:1635–6. https://doi.org/10.1126/science.1071553.
Walczak H. TNF and ubiquitin at the crossroads of gene activation, cell death, inflammation, and cancer. Immunol Rev. 2011;244:9–28. https://doi.org/10.1111/j.1600-065X.2011.01066.x.
Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature. 2016;529:326–35. https://doi.org/10.1038/nature17041.
Wang XZ, Ron D. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Science. 1996;272:1347–9. https://doi.org/10.1126/science.272.5266.1347.
Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science. 1998;281:1680–3. https://doi.org/10.1126/science.281.5383.1680.
Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways. Cell. 2008;133:693–703. https://doi.org/10.1016/j.cell.2008.03.036.
Wang Y, Dawson VL, Dawson TM. Poly(ADP-ribose) signals to mitochondrial AIF: a key event in parthanatos. Exp Neurol. 2009;218:193–202. https://doi.org/10.1016/j.expneurol.2009.03.020.
Wang Y, Gu X, Li W, Zhang Q, Zhang C. PAK1 overexpression promotes cell proliferation in cutaneous T cell lymphoma via suppression of PUMA and p21. J Dermatol Sci. 2018;90:60–7. https://doi.org/10.1016/j.jdermsci.2017.11.019.
Wilson NS, Dixit V, Ashkenazi A. Death receptor signal transducers: nodes of coordination in immune signaling networks. Nat Immunol. 2009;10:348–55. https://doi.org/10.1038/ni.1714.
Wu C-J, Conze DB, Li T, Srinivasula SM, Ashwell JD. Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]. Nat Cell Biol. 2006;8:398–406. https://doi.org/10.1038/ncb1384.
Wu P-K, Hong S-K, Yoon S-H, Park J-I. Active ERK2 is sufficient to mediate growth arrest and differentiation signaling. FEBS J. 2015;282:1017–30. https://doi.org/10.1111/febs.13197.
Wu S, Zhang W, Ma S, Li B, Xu C, Yi P. ERK1/2 and JNK signaling synergistically modulate mitogenic effect of fibroblast growth factor 2 on liver cell. Cell Biol Int. 2018;42:1511–22. https://doi.org/10.1002/cbin.11043.
Wullaert A, Heyninck K, Beyaert R. Mechanisms of crosstalk between TNF-induced NF-kappaB and JNK activation in hepatocytes. Biochem Pharmacol. 2006;72:1090–101. https://doi.org/10.1016/j.bcp.2006.07.003.
Wyrsch P, Blenn C, Bader J, Althaus FR. Cell death and autophagy under oxidative stress: roles of poly(ADP-Ribose) polymerases and Ca(2+). Mol Cell Biol. 2012;32:3541–53. https://doi.org/10.1128/MCB.00437-12.
Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, Takeda K, Akira S. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol. 2002;169:6668–72. https://doi.org/10.4049/jimmunol.169.12.6668.
Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol. 2003;4:1144–50. https://doi.org/10.1038/ni986.
Yang X, Khosravi-Far R, Chang HY, Baltimore D. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell. 1997;89:1067–76. https://doi.org/10.1016/s0092-8674(00)80294-9.
Yang Q, Kim Y-S, Lin Y, Lewis J, Neckers L, Liu Z-G. Tumour necrosis factor receptor 1 mediates endoplasmic reticulum stress-induced activation of the MAP kinase JNK. EMBO Rep. 2006;7:622–7. https://doi.org/10.1038/sj.embor.7400687.
Yao J, Kim TW, Qin J, Jiang Z, Qian Y, Xiao H, Lu Y, Qian W, Gulen MF, Sizemore N, DiDonato J, Sato S, Akira S, Su B, Li X. Interleukin-1 (IL-1)-induced TAK1-dependent versus MEKK3-dependent NFkappaB activation pathways bifurcate at IL-1 receptor-associated kinase modification. J Biol Chem. 2007;282:6075–89. https://doi.org/10.1074/jbc.M609039200.
Ying W. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal. 2008;10:179–206. https://doi.org/10.1089/ars.2007.1672.
Yoo HJ, Byun H-J, Kim B-R, Lee KH, Park S-Y, Rho SB. DAPk1 inhibits NF-κB activation through TNF-α and INF-γ-induced apoptosis. Cell Signal. 2012;24:1471–7. https://doi.org/10.1016/j.cellsig.2012.03.010.
Zeke A, Misheva M, Reményi A, Bogoyevitch MA. JNK signaling: regulation and functions based on complex protein-protein partnerships. Microbiol Mol Biol Rev. 2016;80:793–835. https://doi.org/10.1128/MMBR.00043-14.
Zhang J, Cado D, Chen A, Kabra NH, Winoto A. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature. 1998;392:296–300. https://doi.org/10.1038/32681.
Zhang SQ, Kovalenko A, Cantarella G, Wallach D. Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation. Immunity. 2000;12:301–11. https://doi.org/10.1016/s1074-7613(00)80183-1.
Zhang L, Blackwell K, Shi Z, Habelhah H. The RING domain of TRAF2 plays an essential role in the inhibition of TNFalpha-induced cell death but not in the activation of NF-kappaB. J Mol Biol. 2010;396:528–39. https://doi.org/10.1016/j.jmb.2010.01.008.
Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL, Ron D. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 1998;12:982–95. https://doi.org/10.1101/gad.12.7.982.
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Engin, A. (2021). Protein Kinase-Mediated Decision Between the Life and Death. In: Engin, A.B., Engin, A. (eds) Protein Kinase-mediated Decisions Between Life and Death. Advances in Experimental Medicine and Biology, vol 1275. Springer, Cham. https://doi.org/10.1007/978-3-030-49844-3_1
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