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Receptor (TNFRSF)-interacting serine-threonine kinase 1
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols RIPK1 ; RIP; RIP1
External IDs OMIM603453 MGI108212 HomoloGene2820 IUPHAR: 2189 ChEMBL: 5464 GeneCards: RIPK1 Gene
EC number
RNA expression pattern
PBB GE RIPK1 209941 at tn.png
More reference expression data
Species Human Mouse
Entrez 8737 19766
Ensembl ENSG00000137275 ENSMUSG00000021408
UniProt Q13546 Q60855
RefSeq (mRNA) NM_003804 NM_009068
RefSeq (protein) NP_003795 NP_033094
Location (UCSC) Chr 6:
3.06 – 3.12 Mb
Chr 13:
34 – 34.04 Mb
PubMed search [1] [2]

Receptor-interacting serine/threonine-protein kinase 1 is an enzyme that in humans is encoded by the RIPK1 gene.[1][2][3] RIPK1 is known to have function in a variety of cellular pathways including the NF-κB pathway and programmed necrotic cell death (necroptosis).


Although, RIPK1 has been primarily studied in the context of TNFR signaling, RIPk1 is also activated in response to diverse stimuli.[4]

The kinase domain, while important for necroptotic (programmed necrotic) functions, it appears dispensable for pro-survival roles. Kinase activity of RIPK1 is also required for RIPK1-dependent apoptosis in conditions of IAP1/2 depletion, TAK1inhibition/depletion, RIPK3 depletion or MLKL depletion.[5][6] Also, proteolytic processing of RIPk1, through both caspase-dependent and -independent mechanisms, triggers lethality that is dependent on the generation of one or more specific C-terminal cleavage product(s) of RIPk1 upon stress.


RIPK1 has been shown to interact with:


  1. ^ Stanger BZ, Leder P, Lee TH, Kim E, Seed B (June 1995). "RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death". Cell 81 (4): 513–23. doi:10.1016/0092-8674(95)90072-1. PMID 7538908. 
  2. ^ a b c d Hsu H, Huang J, Shu HB, Baichwal V, Goeddel DV (June 1996). "TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex". Immunity 4 (4): 387–96. doi:10.1016/S1074-7613(00)80252-6. PMID 8612133. 
  3. ^ "Entrez Gene: RIPK1 receptor (TNFRSF)-interacting serine-threonine kinase 1". 
  4. ^ Vanlangenakker N, Vanden Berghe T, Vandenabeele P (January 2012). "Many stimuli pull the necrotic trigger, an overview". Cell Death Differ. 19 (1): 75–86. doi:10.1038/cdd.2011.164. PMC 3252835. PMID 22075985. 
  5. ^ Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C, Grootjans S, Dejardin E, Vandenabeele P, Bertrand MJ.RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1/2 depletion or TAK1 kinase inhibition.Cell Death Differ. 2013 Oct;20(10):1381-92. doi: 10.1038/cdd.2013.94. Epub 2013 Jul 26.PMID 23892367
  6. ^ Remijsen Q1, Goossens V1, Grootjans S1, Van den Haute C2, Vanlangenakker N1, Dondelinger Y1, Roelandt R1, Bruggeman I1, Goncalves A3, Bertrand MJ1, Baekelandt V2, Takahashi N1, Berghe TV1, Vandenabeele P1.Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis.Cell Death Dis. 2014 Jan 16;5:e1004. doi: 10.1038/cddis.2013.531.
  7. ^ a b c d Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J, Gillard JW, Jaquith JB, Morris SJ, Barker PA (June 2008). "cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination". Mol. Cell 30 (6): 689–700. doi:10.1016/j.molcel.2008.05.014. PMID 18570872. 
  8. ^ a b Liao W, Xiao Q, Tchikov V, Fujita K, Yang W, Wincovitch S, Garfield S, Conze D, El-Deiry WS, Schütze S, Srinivasula SM (May 2008). "CARP-2 is an endosome-associated ubiquitin ligase for RIP and regulates TNF-induced NF-kappaB activation". Curr. Biol. 18 (9): 641–9. doi:10.1016/j.cub.2008.04.017. PMC 2587165. PMID 18450452. 
  9. ^ a b Chaudhary PM, Eby MT, Jasmin A, Kumar A, Liu L, Hood L (September 2000). "Activation of the NF-kappaB pathway by caspase 8 and its homologs". Oncogene 19 (39): 4451–60. doi:10.1038/sj.onc.1203812. PMID 11002417. 
  10. ^ Oshima S, Turer EE, Callahan JA, Chai S, Advincula R, Barrera J, Shifrin N, Lee B, Benedict Yen TS, Yen B, Woo T, Malynn BA, Ma A (February 2009). "ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development". Nature 457 (7231): 906–9. doi:10.1038/nature07575. PMC 2642523. PMID 19060883. 
  11. ^ Kataoka T, Budd RC, Holler N, Thome M, Martinon F, Irmler M, Burns K, Hahne M, Kennedy N, Kovacsovics M, Tschopp J (June 2000). "The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways". Curr. Biol. 10 (11): 640–8. doi:10.1016/S0960-9822(00)00512-1. PMID 10837247. 
  12. ^ a b Duan H, Dixit VM (January 1997). "RAIDD is a new 'death' adaptor molecule". Nature 385 (6611): 86–9. doi:10.1038/385086a0. PMID 8985253. 
  13. ^ Ahmad M, Srinivasula SM, Wang L, Talanian RV, Litwack G, Fernandes-Alnemri T, Alnemri ES (February 1997). "CRADD, a novel human apoptotic adaptor molecule for caspase-2, and FasL/tumor necrosis factor receptor-interacting protein RIP". Cancer Res. 57 (4): 615–9. PMID 9044836. 
  14. ^ Yu PW, Huang BC, Shen M, Quast J, Chan E, Xu X, Nolan GP, Payan DG, Luo Y (May 1999). "Identification of RIP3, a RIP-like kinase that activates apoptosis and NFkappaB". Curr. Biol. 9 (10): 539–42. doi:10.1016/S0960-9822(99)80239-5. PMID 10339433. 
  15. ^ Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A, Chan FK, Wu H (July 2012). "The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis". Cell 150 (2): 339–50. doi:10.1016/j.cell.2012.06.019. PMC 3664196. PMID 22817896. 
  16. ^ Shembade N, Parvatiyar K, Harhaj NS, Harhaj EW (March 2009). "The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kappaB signalling". EMBO J. 28 (5): 513–22. doi:10.1038/emboj.2008.285. PMC 2657574. PMID 19131965. 
  17. ^ Chen D, Li X, Zhai Z, Shu HB (May 2002). "A novel zinc finger protein interacts with receptor-interacting protein (RIP) and inhibits tumor necrosis factor (TNF)- and IL1-induced NF-kappa B activation". J. Biol. Chem. 277 (18): 15985–91. doi:10.1074/jbc.M108675200. PMID 11854271. 
  18. ^ Sanz L, Sanchez P, Lallena MJ, Diaz-Meco MT, Moscat J (June 1999). "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation". EMBO J. 18 (11): 3044–53. doi:10.1093/emboj/18.11.3044. PMC 1171386. PMID 10356400. 
  19. ^ Kim JW, Choi EJ, Joe CO (September 2000). "Activation of death-inducing signaling complex (DISC) by pro-apoptotic C-terminal fragment of RIP". Oncogene 19 (39): 4491–9. doi:10.1038/sj.onc.1203796. PMID 11002422. 
  20. ^ Blankenship JW, Varfolomeev E, Goncharov T, Fedorova AV, Kirkpatrick DS, Izrael-Tomasevic A, Phu L, Arnott D, Aghajan M, Zobel K, Bazan JF, Fairbrother WJ, Deshayes K, Vucic D (January 2009). "Ubiquitin binding modulates IAP antagonist-stimulated proteasomal degradation of c-IAP1 and c-IAP2(1)". Biochem. J. 417 (1): 149–60. doi:10.1042/BJ20081885. PMID 18939944. 
  21. ^ a b Newton K, Matsumoto ML, Wertz IE, Kirkpatrick DS, Lill JR, Tan J, Dugger D, Gordon N, Sidhu SS, Fellouse FA, Komuves L, French DM, Ferrando RE, Lam C, Compaan D, Yu C, Bosanac I, Hymowitz SG, Kelley RF, Dixit VM (August 2008). "Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies". Cell 134 (4): 668–78. doi:10.1016/j.cell.2008.07.039. PMID 18724939. 
  22. ^ a b Varfolomeev E, Goncharov T, Fedorova AV, Dynek JN, Zobel K, Deshayes K, Fairbrother WJ, Vucic D (September 2008). "c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation". J. Biol. Chem. 283 (36): 24295–9. doi:10.1074/jbc.C800128200. PMC 3259840. PMID 18621737. 
  23. ^ Takeuchi M, Rothe M, Goeddel DV (August 1996). "Anatomy of TRAF2. Distinct domains for nuclear factor-kappaB activation and association with tumor necrosis factor signaling proteins". J. Biol. Chem. 271 (33): 19935–42. doi:10.1074/jbc.271.33.19935. PMID 8702708. 
  24. ^ Tada K, Okazaki T, Sakon S, Kobarai T, Kurosawa K, Yamaoka S, Hashimoto H, Mak TW, Yagita H, Okumura K, Yeh WC, Nakano H (September 2001). "Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell death". J. Biol. Chem. 276 (39): 36530–4. doi:10.1074/jbc.M104837200. PMID 11479302. 
  25. ^ Malinin NL, Boldin MP, Kovalenko AV, Wallach D (February 1997). "MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1". Nature 385 (6616): 540–4. doi:10.1038/385540a0. PMID 9020361. 
  26. ^ Ma Q, Zhou L, Shi H, Huo K (June 2008). "NUMBL interacts with TAB2 and inhibits TNFalpha and IL-1beta-induced NF-kappaB activation". Cell. Signal. 20 (6): 1044–51. doi:10.1016/j.cellsig.2008.01.015. PMID 18299187. 

Further reading[edit]