RIPK1

Receptor (TNFRSF)-interacting serine-threonine kinase 1
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 4ITH​, 4ITI​, 4ITJ​, 4NEU​
Identifiers
Symbols	RIPK1 ; RIP; RIP1
External IDs	OMIM: 603453 MGI: 108212 HomoloGene: 2820 ChEMBL: 5464 GeneCards: RIPK1 Gene
EC number	2.7.11.1
Gene ontology Molecular function • protein kinase activity • protein serine/threonine kinase activity • death receptor binding • protein binding • ATP binding • ubiquitin protein ligase binding • protein complex binding • identical protein binding • death domain binding Cellular component • cytoplasm • mitochondrion • cytosol • death-inducing signaling complex • receptor complex • membrane raft • ripoptosome Biological process • positive regulation of protein phosphorylation • toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • apoptotic process • activation of cysteine-type endopeptidase activity involved in apoptotic process • cell surface receptor signaling pathway • activation of JUN kinase activity • regulation of necrotic cell death • programmed cell death • positive regulation of type I interferon production • positive regulation of interleukin-8 production • positive regulation of tumor necrosis factor production • tumor necrosis factor-mediated signaling pathway • toll-like receptor 3 signaling pathway • toll-like receptor 4 signaling pathway • response to tumor necrosis factor • TRIF-dependent toll-like receptor signaling pathway • peptidyl-serine autophosphorylation • positive regulation of apoptotic process • positive regulation of programmed cell death • positive regulation of I-kappaB kinase/NF-kappaB signaling • negative regulation of I-kappaB kinase/NF-kappaB signaling • negative regulation of cysteine-type endopeptidase activity involved in apoptotic process • cellular protein catabolic process • innate immune response • positive regulation of macrophage differentiation • positive regulation of transcription from RNA polymerase II promoter • positive regulation of JNK cascade • protein autophosphorylation • positive regulation of NF-kappaB transcription factor activity • protein homooligomerization • protein heterooligomerization • positive regulation of necroptotic process • T cell apoptotic process • necroptotic process • regulation of ATP:ADP antiporter activity • cellular response to tumor necrosis factor • cellular response to growth factor stimulus • death-inducing signaling complex assembly • extrinsic apoptotic signaling pathway • activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway • programmed necrotic cell death • ripoptosome assembly • necroptotic signaling pathway • ripoptosome assembly involved in necroptotic process • regulation of extrinsic apoptotic signaling pathway via death domain receptors • amyloid fibril formation • positive regulation of reactive oxygen species metabolic process • negative regulation of extrinsic apoptotic signaling pathway • positive regulation of extrinsic apoptotic signaling pathway • negative regulation of extrinsic apoptotic signaling pathway in absence of ligand Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
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

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).

Function

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.

Interactions

RIPK1 has been shown to interact with:

• BIRC2,^[7]
• BIRC3,^[7]
• CA11,^[8]
• CASP8,^[7][9][10]
• CFLAR,^[9][11]
• CRADD,^[12][13]
• RIPK3,^[14][15]
• RNF11,^[16]
• RNF216,^[17]
• SQSTM1,^[18]
• TNFRSF1A,^{[2][12][19][20][21][22]}
• TRADD,^[2]
• TRAF2,^{[2][23][24][25]} and
• UBC.^{[7][8][21][22][26]}

References

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. 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 (Oct 2013). "RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1/2 depletion or TAK1 kinase inhibition". Cell Death Differ 20 (10): 1381–92. doi:10.1038/cdd.2013.94. PMID 23892367.
6. Remijsen, Q; Goossens, V; Grootjans, S; Van; den Haute, C; Vanlangenakker, N; Dondelinger, Y; Roelandt, R; Bruggeman, I; Goncalves, A; Bertrand, MJ; Baekelandt, V; Takahashi, N; Berghe, TV; Vandenabeele, P (Jan 2014). "Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis". Cell Death Dis. 5 (1): e1004. doi:10.1038/cddis.2013.531.
7. 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. 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. 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. 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. 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. 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

• Festjens N, Vanden Berghe T, Cornelis S, Vandenabeele P (March 2007). "RIP1, a kinase on the crossroads of a cell's decision to live or die". Cell Death Differ. 14 (3): 400–10. doi:10.1038/sj.cdd.4402085. PMID 17301840.
• Duan H, Dixit VM (January 1997). "RAIDD is a new 'death' adaptor molecule". Nature 385 (6611): 86–9. doi:10.1038/385086a0. PMID 8985253.
• Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J, Hood L (December 1997). "Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway". Immunity 7 (6): 821–30. doi:10.1016/S1074-7613(00)80400-8. PMID 9430227.
• Juo P, Kuo CJ, Yuan J, Blenis J (September 1998). "Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade". Curr. Biol. 8 (18): 1001–8. doi:10.1016/S0960-9822(07)00420-4. PMID 9740801.
• Li Y, Kang J, Friedman J, Tarassishin L, Ye J, Kovalenko A, Wallach D, Horwitz MS (February 1999). "Identification of a cell protein (FIP-3) as a modulator of NF-kappaB activity and as a target of an adenovirus inhibitor of tumor necrosis factor alpha-induced apoptosis". Proc. Natl. Acad. Sci. U.S.A. 96 (3): 1042–7. doi:10.1073/pnas.96.3.1042. PMC 15347. PMID 9927690.
• Sun X, Lee J, Navas T, Baldwin DT, Stewart TA, Dixit VM (June 1999). "RIP3, a novel apoptosis-inducing kinase". J. Biol. Chem. 274 (24): 16871–5. doi:10.1074/jbc.274.24.16871. PMID 10358032.
• Izumi KM, Cahir McFarland ED, Ting AT, Riley EA, Seed B, Kieff ED (August 1999). "The Epstein-Barr virus oncoprotein latent membrane protein 1 engages the tumor necrosis factor receptor-associated proteins TRADD and receptor-interacting protein (RIP) but does not induce apoptosis or require RIP for NF-kappaB activation". Mol. Cell. Biol. 19 (8): 5759–67. PMC 84426. PMID 10409763.
• Lin Y, Devin A, Rodriguez Y, Liu ZG (October 1999). "Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis". Genes Dev. 13 (19): 2514–26. doi:10.1101/gad.13.19.2514. PMC 317073. PMID 10521396.
• Chaudhary PM, Jasmin A, Eby MT, Hood L (October 1999). "Modulation of the NF-kappa B pathway by virally encoded death effector domains-containing proteins". Oncogene 18 (42): 5738–46. doi:10.1038/sj.onc.1202976. PMID 10523854.
• Lewis J, Devin A, Miller A, Lin Y, Rodriguez Y, Neckers L, Liu ZG (April 2000). "Disruption of hsp90 function results in degradation of the death domain kinase, receptor-interacting protein (RIP), and blockage of tumor necrosis factor-induced nuclear factor-kappaB activation". J. Biol. Chem. 275 (14): 10519–26. doi:10.1074/jbc.275.14.10519. PMID 10744744.
• Inohara N, Koseki T, Lin J, del Peso L, Lucas PC, Chen FF, Ogura Y, Núñez G (September 2000). "An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways". J. Biol. Chem. 275 (36): 27823–31. doi:10.1074/jbc.M003415200. PMID 10880512.