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Pathway Description
Necroptosis
Homo sapiens
Signaling Pathway
Created: 2025-03-27
Last Updated: 2025-04-08
Necroptosis is initiated by the activation of death receptors such as TNF receptors (TNFRSF1A and TNFRSF10A) and FAS (TNFRSF6). When these receptors are activated by their ligands, they recruit FADD and activate RIPK1. RIPK1 can then engage with RIPK3, forming the RIPK1-RIPK3 complex, which is crucial for driving necroptosis. Additionally, the MLKL protein is activated via phosphorylation by the RIPK1-RIPK3 complex. Once phosphorylated, MLKL translocates to the plasma membrane, where it disrupts membrane integrity, leading to the characteristic features of necroptosis, such as cell swelling, membrane rupture, and release of intracellular contents. Moreover, interferons, such as interferon alpha, can also influence necroptotic signaling through the JAK1-STAT1 pathway, contributing to inflammation and immune responses. The TRPM7 ion channel is also implicated in necroptosis by mediating calcium influx, which can further activate necroptotic pathways.
References
Necroptosis References
Dhuriya, Y.K., Sharma, D. Necroptosis: a regulated inflammatory mode of cell death. J Neuroinflammation 15, 199 (2018). https://doi.org/10.1186/s12974-018-1235-0
Bertheloot, D., Latz, E. & Franklin, B.S. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. Cell Mol Immunol 18, 1106–1121 (2021). https://doi.org/10.1038/s41423-020-00630-3
Hsu H, Huang J, Shu HB, Baichwal V, Goeddel DV: TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity. 1996 Apr;4(4):387-96.
Pubmed: 8612133
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Mungall AJ, Palmer SA, Sims SK, Edwards CA, Ashurst JL, Wilming L, Jones MC, Horton R, Hunt SE, Scott CE, Gilbert JG, Clamp ME, Bethel G, Milne S, Ainscough R, Almeida JP, Ambrose KD, Andrews TD, Ashwell RI, Babbage AK, Bagguley CL, Bailey J, Banerjee R, Barker DJ, Barlow KF, Bates K, Beare DM, Beasley H, Beasley O, Bird CP, Blakey S, Bray-Allen S, Brook J, Brown AJ, Brown JY, Burford DC, Burrill W, Burton J, Carder C, Carter NP, Chapman JC, Clark SY, Clark G, Clee CM, Clegg S, Cobley V, Collier RE, Collins JE, Colman LK, Corby NR, Coville GJ, Culley KM, Dhami P, Davies J, Dunn M, Earthrowl ME, Ellington AE, Evans KA, Faulkner L, Francis MD, Frankish A, Frankland J, French L, Garner P, Garnett J, Ghori MJ, Gilby LM, Gillson CJ, Glithero RJ, Grafham DV, Grant M, Gribble S, Griffiths C, Griffiths M, Hall R, Halls KS, Hammond S, Harley JL, Hart EA, Heath PD, Heathcott R, Holmes SJ, Howden PJ, Howe KL, Howell GR, Huckle E, Humphray SJ, Humphries MD, Hunt AR, Johnson CM, Joy AA, Kay M, Keenan SJ, Kimberley AM, King A, Laird GK, Langford C, Lawlor S, Leongamornlert DA, Leversha M, Lloyd CR, Lloyd DM, Loveland JE, Lovell J, Martin S, Mashreghi-Mohammadi M, Maslen GL, Matthews L, McCann OT, McLaren SJ, McLay K, McMurray A, Moore MJ, Mullikin JC, Niblett D, Nickerson T, Novik KL, Oliver K, Overton-Larty EK, Parker A, Patel R, Pearce AV, Peck AI, Phillimore B, Phillips S, Plumb RW, Porter KM, Ramsey Y, Ranby SA, Rice CM, Ross MT, Searle SM, Sehra HK, Sheridan E, Skuce CD, Smith S, Smith M, Spraggon L, Squares SL, Steward CA, Sycamore N, Tamlyn-Hall G, Tester J, Theaker AJ, Thomas DW, Thorpe A, Tracey A, Tromans A, Tubby B, Wall M, Wallis JM, West AP, White SS, Whitehead SL, Whittaker H, Wild A, Willey DJ, Wilmer TE, Wood JM, Wray PW, Wyatt JC, Young L, Younger RM, Bentley DR, Coulson A, Durbin R, Hubbard T, Sulston JE, Dunham I, Rogers J, Beck S: The DNA sequence and analysis of human chromosome 6. Nature. 2003 Oct 23;425(6960):805-11. doi: 10.1038/nature02055.
Pubmed: 14574404
Alderson MR, Tough TW, Davis-Smith T, Braddy S, Falk B, Schooley KA, Goodwin RG, Smith CA, Ramsdell F, Lynch DH: Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med. 1995 Jan 1;181(1):71-7. doi: 10.1084/jem.181.1.71.
Pubmed: 7528780
Takahashi T, Tanaka M, Inazawa J, Abe T, Suda T, Nagata S: Human Fas ligand: gene structure, chromosomal location and species specificity. Int Immunol. 1994 Oct;6(10):1567-74. doi: 10.1093/intimm/6.10.1567.
Pubmed: 7826947
Mita E, Hayashi N, Iio S, Takehara T, Hijioka T, Kasahara A, Fusamoto H, Kamada T: Role of Fas ligand in apoptosis induced by hepatitis C virus infection. Biochem Biophys Res Commun. 1994 Oct 28;204(2):468-74. doi: 10.1006/bbrc.1994.2483.
Pubmed: 7980502
Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S: The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991 Jul 26;66(2):233-43. doi: 10.1016/0092-8674(91)90614-5.
Pubmed: 1713127
Oehm A, Behrmann I, Falk W, Pawlita M, Maier G, Klas C, Li-Weber M, Richards S, Dhein J, Trauth BC, et al.: Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Sequence identity with the Fas antigen. J Biol Chem. 1992 May 25;267(15):10709-15.
Pubmed: 1375228
Liu C, Cheng J, Mountz JD: Differential expression of human Fas mRNA species upon peripheral blood mononuclear cell activation. Biochem J. 1995 Sep 15;310 ( Pt 3):957-63. doi: 10.1042/bj3100957.
Pubmed: 7575433
Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM: FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell. 1995 May 19;81(4):505-12. doi: 10.1016/0092-8674(95)90071-3.
Pubmed: 7538907
Rochat-Steiner V, Becker K, Micheau O, Schneider P, Burns K, Tschopp J: FIST/HIPK3: a Fas/FADD-interacting serine/threonine kinase that induces FADD phosphorylation and inhibits fas-mediated Jun NH(2)-terminal kinase activation. J Exp Med. 2000 Oct 16;192(8):1165-74. doi: 10.1084/jem.192.8.1165.
Pubmed: 11034606
Bolze A, Byun M, McDonald D, Morgan NV, Abhyankar A, Premkumar L, Puel A, Bacon CM, Rieux-Laucat F, Pang K, Britland A, Abel L, Cant A, Maher ER, Riedl SJ, Hambleton S, Casanova JL: Whole-exome-sequencing-based discovery of human FADD deficiency. Am J Hum Genet. 2010 Dec 10;87(6):873-81. doi: 10.1016/j.ajhg.2010.10.028. Epub 2010 Nov 25.
Pubmed: 21109225
Uze G, Lutfalla G, Gresser I: Genetic transfer of a functional human interferon alpha receptor into mouse cells: cloning and expression of its cDNA. Cell. 1990 Jan 26;60(2):225-34. doi: 10.1016/0092-8674(90)90738-z.
Pubmed: 2153461
Lutfalla G, Gardiner K, Proudhon D, Vielh E, Uze G: The structure of the human interferon alpha/beta receptor gene. J Biol Chem. 1992 Feb 5;267(4):2802-9.
Pubmed: 1370833
Williams NK, Bamert RS, Patel O, Wang C, Walden PM, Wilks AF, Fantino E, Rossjohn J, Lucet IS: Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J Mol Biol. 2009 Mar 20;387(1):219-32. doi: 10.1016/j.jmb.2009.01.041. Epub 2009 Jan 29.
Pubmed: 19361440
Wilks AF, Harpur AG, Kurban RR, Ralph SJ, Zurcher G, Ziemiecki A: Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol Cell Biol. 1991 Apr;11(4):2057-65. doi: 10.1128/mcb.11.4.2057.
Pubmed: 1848670
Gregory SG, Barlow KF, McLay KE, Kaul R, Swarbreck D, Dunham A, Scott CE, Howe KL, Woodfine K, Spencer CC, Jones MC, Gillson C, Searle S, Zhou Y, Kokocinski F, McDonald L, Evans R, Phillips K, Atkinson A, Cooper R, Jones C, Hall RE, Andrews TD, Lloyd C, Ainscough R, Almeida JP, Ambrose KD, Anderson F, Andrew RW, Ashwell RI, Aubin K, Babbage AK, Bagguley CL, Bailey J, Beasley H, Bethel G, Bird CP, Bray-Allen S, Brown JY, Brown AJ, Buckley D, Burton J, Bye J, Carder C, Chapman JC, Clark SY, Clarke G, Clee C, Cobley V, Collier RE, Corby N, Coville GJ, Davies J, Deadman R, Dunn M, Earthrowl M, Ellington AG, Errington H, Frankish A, Frankland J, French L, Garner P, Garnett J, Gay L, Ghori MR, Gibson R, Gilby LM, Gillett W, Glithero RJ, Grafham DV, Griffiths C, Griffiths-Jones S, Grocock R, Hammond S, Harrison ES, Hart E, Haugen E, Heath PD, Holmes S, Holt K, Howden PJ, Hunt AR, Hunt SE, Hunter G, Isherwood J, James R, Johnson C, Johnson D, Joy A, Kay M, Kershaw JK, Kibukawa M, Kimberley AM, King A, Knights AJ, Lad H, Laird G, Lawlor S, Leongamornlert DA, Lloyd DM, Loveland J, Lovell J, Lush MJ, Lyne R, Martin S, Mashreghi-Mohammadi M, Matthews L, Matthews NS, McLaren S, Milne S, Mistry S, Moore MJ, Nickerson T, O'Dell CN, Oliver K, Palmeiri A, Palmer SA, Parker A, Patel D, Pearce AV, Peck AI, Pelan S, Phelps K, Phillimore BJ, Plumb R, Rajan J, Raymond C, Rouse G, Saenphimmachak C, Sehra HK, Sheridan E, Shownkeen R, Sims S, Skuce CD, Smith M, Steward C, Subramanian S, Sycamore N, Tracey A, Tromans A, Van Helmond Z, Wall M, Wallis JM, White S, Whitehead SL, Wilkinson JE, Willey DL, Williams H, Wilming L, Wray PW, Wu Z, Coulson A, Vaudin M, Sulston JE, Durbin R, Hubbard T, Wooster R, Dunham I, Carter NP, McVean G, Ross MT, Harrow J, Olson MV, Beck S, Rogers J, Bentley DR, Banerjee R, Bryant SP, Burford DC, Burrill WD, Clegg SM, Dhami P, Dovey O, Faulkner LM, Gribble SM, Langford CF, Pandian RD, Porter KM, Prigmore E: The DNA sequence and biological annotation of human chromosome 1. Nature. 2006 May 18;441(7091):315-21. doi: 10.1038/nature04727.
Pubmed: 16710414
Rogers RS, Horvath CM, Matunis MJ: SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation. J Biol Chem. 2003 Aug 8;278(32):30091-7. doi: 10.1074/jbc.M301344200. Epub 2003 May 22.
Pubmed: 12764129
Schindler C, Fu XY, Improta T, Aebersold R, Darnell JE Jr: Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7836-9. doi: 10.1073/pnas.89.16.7836.
Pubmed: 1502203
Neville MJ, Campbell RD: A new member of the Ig superfamily and a V-ATPase G subunit are among the predicted products of novel genes close to the TNF locus in the human MHC. J Immunol. 1999 Apr 15;162(8):4745-54.
Pubmed: 10202016
Van Ostade X, Tavernier J, Prange T, Fiers W: Localization of the active site of human tumour necrosis factor (hTNF) by mutational analysis. EMBO J. 1991 Apr;10(4):827-36.
Pubmed: 2009860
Friedmann E, Hauben E, Maylandt K, Schleeger S, Vreugde S, Lichtenthaler SF, Kuhn PH, Stauffer D, Rovelli G, Martoglio B: SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production. Nat Cell Biol. 2006 Aug;8(8):843-8. doi: 10.1038/ncb1440. Epub 2006 Jul 9.
Pubmed: 16829952
Loetscher H, Pan YC, Lahm HW, Gentz R, Brockhaus M, Tabuchi H, Lesslauer W: Molecular cloning and expression of the human 55 kd tumor necrosis factor receptor. Cell. 1990 Apr 20;61(2):351-9. doi: 10.1016/0092-8674(90)90815-v.
Pubmed: 2158862
Schall TJ, Lewis M, Koller KJ, Lee A, Rice GC, Wong GH, Gatanaga T, Granger GA, Lentz R, Raab H, et al.: Molecular cloning and expression of a receptor for human tumor necrosis factor. Cell. 1990 Apr 20;61(2):361-70. doi: 10.1016/0092-8674(90)90816-w.
Pubmed: 2158863
Himmler A, Maurer-Fogy I, Kronke M, Scheurich P, Pfizenmaier K, Lantz M, Olsson I, Hauptmann R, Stratowa C, Adolf GR: Molecular cloning and expression of human and rat tumor necrosis factor receptor chain (p60) and its soluble derivative, tumor necrosis factor-binding protein. DNA Cell Biol. 1990 Dec;9(10):705-15. doi: 10.1089/dna.1990.9.705.
Pubmed: 1702293
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