KEGG   PATHWAY: fpg04217
Entry
fpg04217                    Pathway                                
Name
Necroptosis - Falco peregrinus (peregrine falcon)
Description
Necroptosis is a programmed form of necrosis. It can be initiated by different stimuli, such as tumor necrosis factor (TNF), TNF-related apoptosis-inducing ligand (TRAIL), Fas ligand (FasL), interferon (IFN), LPS, viral DNA or RNA, DNA-damage agent and requires the kinase activity of receptor-interacting protein 1 (RIPK1) and RIPK3. Its execution involves ROS generation, calcium overload, the opening of the mitochondrial permeability transition pore, mitochondrial fission, inflammatory response and chromatinolysis. Necroptosis participates in many pathogenesis of diseases, including neurological diseases, retinal disorders, acute kidney injury, inflammatory diseases and microbial infections.
Class
Cellular Processes; Cell growth and death
Pathway map
fpg04217  Necroptosis
fpg04217

Organism
Falco peregrinus (peregrine falcon) [GN:fpg]
Gene
101917376  TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158]
101921498  TRADD; TNFRSF1A associated via death domain [KO:K03171]
101911961  TRAF2; TNF receptor associated factor 2 [KO:K03173] [EC:2.3.2.27]
101921400  TRAF5; TNF receptor associated factor 5 [KO:K09849]
101913441  RIPK1; receptor interacting serine/threonine kinase 1 [KO:K02861] [EC:2.7.11.1]
101924079  BIRC2; baculoviral IAP repeat containing 2 [KO:K16060]
101916449  XIAP; X-linked inhibitor of apoptosis [KO:K04725] [EC:2.3.2.27]
101917453  SHARPIN; SHANK associated RH domain interactor [KO:K10630] [EC:2.3.2.31]
106112442  uncharacterized LOC106112442 [KO:K17595]
101923053  SPATA2; spermatogenesis associated 2 [KO:K17595]
106112386  SPATA2L; spermatogenesis associated 2 like [KO:K17595]
101918460  ubiquitin carboxyl-terminal hydrolase CYLD-like [KO:K08601] [EC:3.4.19.12]
101912553  CYLD; CYLD lysine 63 deubiquitinase [KO:K08601] [EC:3.4.19.12]
101918701  FADD; Fas associated via death domain [KO:K02373]
106113022  CASP8 and FADD-like apoptosis regulator [KO:K04398] [EC:3.4.22.61]
101916968  CASP8; caspase-3 [KO:K04398] [EC:3.4.22.61]
101916800  CFLAR; CASP8 and FADD like apoptosis regulator [KO:K04724]
101920108  cytochrome b-245 heavy chain [KO:K21421] [EC:1.-.-.-]
101918953  CAMK2A; calcium/calmodulin dependent protein kinase II alpha [KO:K04515] [EC:2.7.11.17]
101915367  CAMK2G; calcium/calmodulin dependent protein kinase II gamma [KO:K04515] [EC:2.7.11.17]
101923748  CAMK2B; calcium/calmodulin dependent protein kinase II beta [KO:K04515] [EC:2.7.11.17]
101914593  CAMK2D; calcium/calmodulin dependent protein kinase II delta [KO:K04515] [EC:2.7.11.17]
101917366  SLC25A6; solute carrier family 25 member 6 [KO:K05863]
101917374  SLC25A4; solute carrier family 25 member 4 [KO:K05863]
101911995  SLC25A5; solute carrier family 25 member 5 [KO:K05863]
101923649  SLC25A31; solute carrier family 25 member 31 [KO:K05863]
101914674  PPID; peptidylprolyl isomerase D [KO:K05864] [EC:5.2.1.8]
101912067  VDAC1; voltage dependent anion channel 1 [KO:K05862]
101915240  VDAC2; voltage dependent anion channel 2 [KO:K15040]
101915493  VDAC3; voltage dependent anion channel 3 [KO:K15041]
101916852  glutamate dehydrogenase 1, mitochondrial-like [KO:K00261] [EC:1.4.1.3]
101919483  GLUD1; glutamate dehydrogenase 1 [KO:K00261] [EC:1.4.1.3]
101915892  glutamine synthetase [KO:K01915] [EC:6.3.1.2]
101918720  GLUL; glutamate-ammonia ligase [KO:K01915] [EC:6.3.1.2]
101912765  PYGL; glycogen phosphorylase L [KO:K00688] [EC:2.4.1.1]
101920493  PYGB; glycogen phosphorylase B [KO:K00688] [EC:2.4.1.1]
101917138  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
101924129  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
101921076  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
101910956  FTH1; ferritin heavy chain 1 [KO:K00522] [EC:1.16.3.1]
101922121  cytosolic phospholipase A2 epsilon-like [KO:K16342] [EC:3.1.1.4]
101920043  cytosolic phospholipase A2 epsilon-like [KO:K16342] [EC:3.1.1.4]
101918580  PLA2G4A; phospholipase A2 group IVA [KO:K16342] [EC:3.1.1.4]
101915779  PLA2G4C; phospholipase A2 group IVC [KO:K16342] [EC:3.1.1.4]
101925028  PLA2G4F; phospholipase A2 group IVF [KO:K16342] [EC:3.1.1.4]
101924845  cytosolic phospholipase A2 epsilon-like [KO:K16342] [EC:3.1.1.4]
101925011  PLA2G4E; cytosolic phospholipase A2 epsilon [KO:K16342] [EC:3.1.1.4]
101922643  PLA2G4B; cytosolic phospholipase A2 beta [KO:K16342] [EC:3.1.1.4]
101911941  CAPN1; calpain 1 [KO:K01367] [EC:3.4.22.52]
101913440  CAPN11; calpain 11 [KO:K01367] [EC:3.4.22.52]
101919959  CAPN2; calpain 2 [KO:K03853] [EC:3.4.22.53]
101921655  SMPD1; sphingomyelin phosphodiesterase 1 [KO:K12350] [EC:3.1.4.12]
101919582  MLKL; mixed lineage kinase domain like pseudokinase [KO:K08849] [EC:2.7.11.1]
101919992  PGAM5; PGAM family member 5, mitochondrial serine/threonine protein phosphatase [KO:K15637] [EC:3.1.3.16]
101921756  DNM1L; dynamin 1 like [KO:K17065] [EC:3.6.5.5]
101918175  NLRP6; NLR family pyrin domain containing 6 [KO:K12800]
101914004  caspase-1-like [KO:K01370] [EC:3.4.22.36]
101924267  interleukin-1 receptor antagonist protein-like [KO:K04519]
101910396  CHMP2A; charged multivesicular body protein 2A [KO:K12191]
101919883  CHMP2B; charged multivesicular body protein 2B [KO:K12192]
101912830  CHMP4B; charged multivesicular body protein 4B [KO:K12194]
101920896  CHMP4C; charged multivesicular body protein 4C [KO:K24782]
101919680  CHMP6; charged multivesicular body protein 6 [KO:K12195]
101912913  VPS4A; vacuolar protein sorting 4 homolog A [KO:K12196]
101922591  VPS4B; vacuolar protein sorting 4 homolog B [KO:K12196]
101918582  CHMP1B; charged multivesicular body protein 1B [KO:K12197]
101922418  CHMP1A; charged multivesicular body protein 1A [KO:K12197]
101916446  CHMP5; charged multivesicular body protein 5 [KO:K12198]
101910983  CHMP7; charged multivesicular body protein 7 [KO:K15053]
101922846  TNFSF10; tumor necrosis factor superfamily member 10 [KO:K04721]
101919474  TNFRSF10A; tumor necrosis factor receptor superfamily member 10A [KO:K04722]
101922036  FASLG; Fas ligand [KO:K04389]
101911760  FAS; Fas cell surface death receptor [KO:K04390]
101915699  IFNW1; interferon omega-1 [KO:K05414]
101921672  interferon-like [KO:K05415]
101924637  IFNG; interferon gamma [KO:K04687]
101919760  IFNAR1; interferon alpha and beta receptor subunit 1 [KO:K05130]
101919412  IFNAR2; interferon alpha and beta receptor subunit 2 [KO:K05131]
101911079  IFNGR1; interferon gamma receptor 1 [KO:K05132]
101919933  IFNGR2; interferon gamma receptor 2 [KO:K05133]
101921412  JAK1; Janus kinase 1 [KO:K11217] [EC:2.7.10.2]
101916887  JAK2; Janus kinase 2 [KO:K04447] [EC:2.7.10.2]
101914306  JAK3; Janus kinase 3 [KO:K11218] [EC:2.7.10.2]
101913479  TYK2; tyrosine kinase 2 [KO:K11219] [EC:2.7.10.2]
101922205  STAT1; signal transducer and activator of transcription 1 [KO:K11220]
101912561  STAT2; signal transducer and activator of transcription 2 [KO:K11221]
101917971  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
101922376  STAT4; signal transducer and activator of transcription 4 [KO:K11222]
101918263  STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
101917515  STAT6; signal transducer and activator of transcription 6 [KO:K11225]
101910588  EIF2AK2; eukaryotic translation initiation factor 2 alpha kinase 2 [KO:K16195] [EC:2.7.11.1]
101922930  TLR4; toll like receptor 4 [KO:K10160]
101917427  TICAM2; toll like receptor adaptor molecule 2 [KO:K05409]
101912470  TICAM1; toll like receptor adaptor molecule 1 [KO:K05842]
101918059  TLR3; toll like receptor 3 [KO:K05401]
101910609  PPOX; uncharacterized LOC101910609 [KO:K21634] [EC:3.4.19.12]
101919269  SQSTM1; sequestosome 1 [KO:K14381]
101913777  HSP90AB1; heat shock protein 90 alpha family class B member 1 [KO:K04079]
101916896  HSP90AA1; heat shock protein 90 alpha family class A member 1 [KO:K04079]
101911730  TNFAIP3; TNF alpha induced protein 3 [KO:K11859] [EC:3.4.19.12]
101914193  PARP1; poly(ADP-ribose) polymerase 1 [KO:K24070] [EC:2.4.2.30]
101917399  BID; BH3 interacting domain death agonist [KO:K04726]
101920283  BAX; BCL2 associated X, apoptosis regulator [KO:K02159]
101923051  AIFM1; apoptosis inducing factor mitochondria associated 1 [KO:K04727] [EC:1.-.-.-]
101913574  histone H2A-beta, sperm-like [KO:K11251]
101921158  histone H2A.V [KO:K11251]
101923645  histone H2A [KO:K11251]
101911108  histone H2A-IV [KO:K11251]
101910375  core histone macro-H2A.1 [KO:K11251]
101911171  histone H2A [KO:K11251]
101914629  histone H2A.Z [KO:K11251]
101918031  core histone macro-H2A.2 [KO:K11251]
101919599  histone H2A type 2-C-like [KO:K11251]
101924665  histone H2A type 2-C-like [KO:K11251]
101924345  histone H2A-IV-like [KO:K11251]
101925005  histone H2A.J-like [KO:K11251]
101919773  histone H2A-like [KO:K11251]
101920120  histone H2A-like [KO:K11251]
106112506  histone H2A-IV-like [KO:K11251]
101920646  PPIA; peptidylprolyl isomerase A [KO:K03767] [EC:5.2.1.8]
101921728  BCL2; BCL2, apoptosis regulator [KO:K02161]
Compound
C00002  ATP
C00027  Hydrogen peroxide
C00076  Calcium cation
C00195  N-Acylsphingosine
C00219  Arachidonate
C00305  Magnesium cation
C00319  Sphingosine
C00550  Sphingomyelin
C14592  N-Methyl-N'-nitro-N-nitrosoguanidine
C16844  Hydroxyl radical
Reference
  Authors
Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G
  Title
Molecular mechanisms of necroptosis: an ordered cellular explosion.
  Journal
Nat Rev Mol Cell Biol 11:700-14 (2010)
DOI:10.1038/nrm2970
Reference
  Authors
Brenner D, Blaser H, Mak TW
  Title
Regulation of tumour necrosis factor signalling: live or let die.
  Journal
Nat Rev Immunol 15:362-74 (2015)
DOI:10.1038/nri3834
Reference
  Authors
Conrad M, Angeli JP, Vandenabeele P, Stockwell BR
  Title
Regulated necrosis: disease relevance and therapeutic opportunities.
  Journal
Nat Rev Drug Discov 15:348-66 (2016)
DOI:10.1038/nrd.2015.6
Reference
  Authors
Ofengeim D, Yuan J
  Title
Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death.
  Journal
Nat Rev Mol Cell Biol 14:727-36 (2013)
DOI:10.1038/nrm3683
Reference
  Authors
Murphy JM, Vince JE
  Title
Post-translational control of RIPK3 and MLKL mediated necroptotic cell death.
  Journal
F1000Res 4:F1000 Faculty Rev-1297 (2015)
DOI:10.12688/f1000research.7046.1
Reference
  Authors
Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P
  Title
Regulated necrosis: the expanding network of non-apoptotic cell death pathways.
  Journal
Nat Rev Mol Cell Biol 15:135-47 (2014)
DOI:10.1038/nrm3737
Reference
  Authors
Dondelinger Y, Hulpiau P, Saeys Y, Bertrand MJ, Vandenabeele P
  Title
An evolutionary perspective on the necroptotic pathway.
  Journal
Trends Cell Biol 26:721-32 (2016)
DOI:10.1016/j.tcb.2016.06.004
Reference
  Authors
Thapa RJ, Ingram JP, Ragan KB, Nogusa S, Boyd DF, Benitez AA, Sridharan H, Kosoff R, Shubina M, Landsteiner VJ, Andrake M, Vogel P, Sigal LJ, tenOever BR, Thomas PG, Upton JW, Balachandran S
  Title
DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death.
  Journal
Cell Host Microbe 20:674-681 (2016)
DOI:10.1016/j.chom.2016.09.014
Reference
  Authors
Yuan J, Najafov A, Py BF
  Title
Roles of Caspases in Necrotic Cell Death.
  Journal
Cell 167:1693-1704 (2016)
DOI:10.1016/j.cell.2016.11.047
Reference
  Authors
Jorgensen I, Rayamajhi M, Miao EA
  Title
Programmed cell death as a defence against infection.
  Journal
Nat Rev Immunol 17:151-164 (2017)
DOI:10.1038/nri.2016.147
Reference
  Authors
Vandenabeele P, Declercq W, Van Herreweghe F, Vanden Berghe T
  Title
The role of the kinases RIP1 and RIP3 in TNF-induced necrosis.
  Journal
Sci Signal 3:re4 (2010)
DOI:10.1126/scisignal.3115re4
Reference
  Authors
Vanlangenakker N, Vanden Berghe T, Vandenabeele P
  Title
Many stimuli pull the necrotic trigger, an overview.
  Journal
Cell Death Differ 19:75-86 (2012)
DOI:10.1038/cdd.2011.164
Reference
  Authors
Moriwaki K, Chan FK
  Title
RIP3: a molecular switch for necrosis and inflammation.
  Journal
Genes Dev 27:1640-9 (2013)
DOI:10.1101/gad.223321.113
Reference
  Authors
Humphries F, Yang S, Wang B, Moynagh PN
  Title
RIP kinases: key decision makers in cell death and innate immunity.
  Journal
Cell Death Differ 22:225-36 (2015)
DOI:10.1038/cdd.2014.126
Reference
  Authors
Wegner KW, Saleh D, Degterev A
  Title
Complex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond Necroptosis.
  Journal
Trends Pharmacol Sci 38:202-225 (2017)
DOI:10.1016/j.tips.2016.12.005
Reference
  Authors
Kupka S, De Miguel D, Draber P, Martino L, Surinova S, Rittinger K, Walczak H
  Title
SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes.
  Journal
Cell Rep 16:2271-80 (2016)
DOI:10.1016/j.celrep.2016.07.086
Reference
  Authors
Goodall ML, Fitzwalter BE, Zahedi S, Wu M, Rodriguez D, Mulcahy-Levy JM, Green DR, Morgan M, Cramer SD, Thorburn A
  Title
The Autophagy Machinery Controls Cell Death Switching between Apoptosis and Necroptosis.
  Journal
Dev Cell 37:337-49 (2016)
DOI:10.1016/j.devcel.2016.04.018
Reference
  Authors
Xu G, Tan X, Wang H, Sun W, Shi Y, Burlingame S, Gu X, Cao G, Zhang T, Qin J, Yang J
  Title
Ubiquitin-specific peptidase 21 inhibits tumor necrosis factor alpha-induced nuclear factor kappaB activation via binding to and deubiquitinating receptor-interacting protein 1.
  Journal
J Biol Chem 285:969-78 (2010)
DOI:10.1074/jbc.M109.042689
Reference
  Authors
Jacobsen AV, Silke J
  Title
The importance of being chaperoned: HSP90 and necroptosis.
  Journal
Cell Chem Biol 23:205-7 (2016)
DOI:10.1016/j.chembiol.2016.02.003
Reference
  Authors
Gurung P, Man SM, Kanneganti TD
  Title
A20 is a regulator of necroptosis.
  Journal
Nat Immunol 16:596-7 (2015)
DOI:10.1038/ni.3174
Reference
  Authors
Feng N, Anderson ME
  Title
CaMKII is a nodal signal for multiple programmed cell death pathways in heart.
  Journal
J Mol Cell Cardiol 103:102-109 (2017)
DOI:10.1016/j.yjmcc.2016.12.007
Reference
  Authors
Zhivotovsky B, Galluzzi L, Kepp O, Kroemer G
  Title
Adenine nucleotide translocase: a component of the phylogenetically conserved cell death machinery.
  Journal
Cell Death Differ 16:1419-25 (2009)
DOI:10.1038/cdd.2009.118
Reference
  Authors
Thapa RJ, Nogusa S, Chen P, Maki JL, Lerro A, Andrake M, Rall GF, Degterev A, Balachandran S
  Title
Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases.
  Journal
Proc Natl Acad Sci U S A 110:E3109-18 (2013)
DOI:10.1073/pnas.1301218110
Reference
  Authors
Thapa RJ, Basagoudanavar SH, Nogusa S, Irrinki K, Mallilankaraman K, Slifker MJ, Beg AA, Madesh M, Balachandran S
  Title
NF-kappaB protects cells from gamma interferon-induced RIP1-dependent necroptosis.
  Journal
Mol Cell Biol 31:2934-46 (2011)
DOI:10.1128/MCB.05445-11
Reference
  Authors
Sridharan H, Upton JW
  Title
Programmed necrosis in microbial pathogenesis.
  Journal
Trends Microbiol 22:199-207 (2014)
DOI:10.1016/j.tim.2014.01.005
Reference
  Authors
Cabon L, Galan-Malo P, Bouharrour A, Delavallee L, Brunelle-Navas MN, Lorenzo HK, Gross A, Susin SA
  Title
BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation.
  Journal
Cell Death Differ 19:245-56 (2012)
DOI:10.1038/cdd.2011.91
Reference
  Authors
Baritaud M, Boujrad H, Lorenzo HK, Krantic S, Susin SA
  Title
Histone H2AX: The missing link in AIF-mediated caspase-independent programmed necrosis.
  Journal
Cell Cycle 9:3166-73 (2010)
DOI:10.4161/cc.9.16.12887
Reference
  Authors
Upton JW, Kaiser WJ
  Title
DAI Another Way: Necroptotic Control of Viral Infection.
  Journal
Cell Host Microbe 21:290-293 (2017)
DOI:10.1016/j.chom.2017.01.016
Reference
  Authors
Silke J, Rickard JA, Gerlic M
  Title
The diverse role of RIP kinases in necroptosis and inflammation.
  Journal
Nat Immunol 16:689-97 (2015)
DOI:10.1038/ni.3206
Reference
  Authors
Guo H, Kaiser WJ
  Title
ESCRTing Necroptosis.
  Journal
Cell 169:186-187 (2017)
DOI:10.1016/j.cell.2017.03.030
Reference
  Authors
Gong YN, Guy C, Olauson H, Becker JU, Yang M, Fitzgerald P, Linkermann A, Green DR
  Title
ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences.
  Journal
Cell 169:286-300.e16 (2017)
DOI:10.1016/j.cell.2017.03.020
Reference
  Authors
Petrie EJ, Hildebrand JM, Murphy JM
  Title
Insane in the membrane: a structural perspective of MLKL function in necroptosis.
  Journal
Immunol Cell Biol 95:152-159 (2017)
DOI:10.1038/icb.2016.125
Reference
  Authors
Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S, Liu J, Ward Y, Wu LG, Liu ZG
  Title
Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis.
  Journal
Nat Cell Biol 16:55-65 (2014)
DOI:10.1038/ncb2883
Reference
  Authors
Lawlor KE, Khan N, Mildenhall A, Gerlic M, Croker BA, D'Cruz AA, Hall C, Kaur Spall S, Anderton H, Masters SL, Rashidi M, Wicks IP, Alexander WS, Mitsuuchi Y, Benetatos CA, Condon SM, Wong WW, Silke J, Vaux DL, Vince JE
  Title
RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL.
  Journal
Nat Commun 6:6282 (2015)
DOI:10.1038/ncomms7282
Reference
  Authors
Shlomovitz I, Zargrian S, Gerlic M
  Title
Mechanisms of RIPK3-induced inflammation.
  Journal
Immunol Cell Biol 95:166-172 (2017)
DOI:10.1038/icb.2016.124
Related
pathway
fpg00250  Alanine, aspartate and glutamate metabolism
fpg04210  Apoptosis
KO pathway
ko04217   
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