Q13546 (RIPK1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Receptor-interacting serine/threonine-protein kinase 1
EC=2.7.11.1

Alternative name(s):
Cell death protein RIP
Receptor-interacting protein 1
Short name=RIP-1
Serine/threonine-protein kinase RIP

Gene names

Name:	RIPK1
Synonyms:	RIP, RIP1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	671 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex. Ref.14 Ref.28 Ref.29
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	Inhibited by necrostatin-1.
Subunit structure	Interacts (via RIP homotypic interaction motif) with RIPK3 (via RIP homotypic interaction motif). Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer further interacts with PGAM5 and MLKL; the formation of this complex leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase activity. Interacts (via the death domain) with TNFRSF6 (via the death domain) and TRADD (via the death domain). Is recruited by TRADD to TNFRSF1A in a TNF-dependent process. Binds RNF216, EGFR, IKBKG, TRAF1, TRAF2 and TRAF3. Interacts with BNLF1. Interacts with SQSTM1 upon TNF-alpha stimulation. May interact with MAVS/IPS1. Interacts with ZFAND5. Interacts with RBCK1 By similarity. Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Upon TNF-induced necrosis, forms in complex with PGAM5, RIPK3 and MLKL. Ref.1 Ref.10 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17 Ref.19 Ref.21 Ref.24 Ref.26 Ref.29 Ref.33 Ref.34
Subcellular location	Cytoplasm. Cell membrane By similarity.
Domain	Contains a C-terminal death domain (DD) that engages other DD-containing proteins as well as a central (intermediate) region important for NF-kB activation and RHIM-dependent signaling. Ref.10
Post-translational modification	Proteolytically cleaved by caspase-8 during TNF-induced apoptosis. Cleavage abolishes NF-kappa-B activation and enhances pro-apoptotic signaling through the TRADD-FADD interaction. Ref.9 RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. Phosphorylation of Ser-161 by RIPK3 is necessary for the formation of the necroptosis-inducing complex. Ubiquitinated by 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-linked type ubiquitin. Polyubiquitination with 'Lys-63'-linked chains by TRAF2 induces association with the IKK complex. Deubiquitination of 'Lys-63'-linked chains and polyubiquitination with 'Lys-48'-linked chains by TNFAIP3 leads to RIPK1 proteasomal degradation and consequently down-regulates TNF-alpha-induced NFkappa-B signaling. Linear polyubiquitinated; the head-to-tail polyubiquitination is mediated by the LUBAC complex. LPS-mediated activation of NF-kappa-B. Also ubiquitinated with 'Lys-11'-linked chains. Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B. Ref.20 Ref.22 Ref.32 Ref.33
Sequence similarities	Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Contains 1 death domain. Contains 1 protein kinase domain.
Sequence caution	The sequence BAG65471.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	Necrosis
Cellular component	Cell membrane Cytoplasm Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	TRIF-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome Toll signaling pathway Traceable author statement. Source: Reactome activation of JUN kinase activity Traceable author statement PubMed 17979836. Source: BHF-UCL activation of cysteine-type endopeptidase activity involved in apoptotic process Traceable author statement. Source: Reactome activation of necroptosis by extracellular signals Inferred from mutant phenotype Ref.14. Source: BHF-UCL cellular protein catabolic process Inferred from direct assay PubMed 17389591. Source: UniProtKB induction of apoptosis Inferred from mutant phenotype Ref.9Ref.1. Source: BHF-UCL innate immune response Traceable author statement. Source: Reactome negative regulation of apoptotic process Traceable author statement PubMed 17979836. Source: BHF-UCL negative regulation of extrinsic apoptotic signaling pathway Inferred from mutant phenotype PubMed 21525013. Source: UniProtKB negative regulation of intrinsic apoptotic signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from direct assay PubMed 17389591. Source: UniProtKB positive regulation of JNK cascade Inferred from direct assay PubMed 17389591. Source: UniProtKB positive regulation of NF-kappaB transcription factor activity Inferred from mutant phenotype Ref.9Ref.1. Source: BHF-UCL positive regulation of extrinsic apoptotic signaling pathway Inferred from mutant phenotype PubMed 21525013PubMed 22274400. Source: UniProtKB positive regulation of interleukin-8 production Inferred from direct assay Ref.21. Source: BHF-UCL positive regulation of reactive oxygen species metabolic process Traceable author statement PubMed 17979836. Source: BHF-UCL positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 17389591. Source: UniProtKB positive regulation of tumor necrosis factor production Inferred from direct assay Ref.21. Source: BHF-UCL positive regulation of type I interferon production Traceable author statement. Source: Reactome protein autophosphorylation Inferred from direct assay Ref.1. Source: BHF-UCL protein heterooligomerization Inferred from electronic annotation. Source: Compara protein homooligomerization Inferred from direct assay PubMed 22817896. Source: UniProtKB regulation of ATP:ADP antiporter activity Inferred from mutant phenotype PubMed 16507998. Source: BHF-UCL toll-like receptor 3 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 4 signaling pathway Traceable author statement. Source: Reactome tumor necrosis factor-mediated signaling pathway Inferred by curator Ref.1. Source: BHF-UCL
Cellular_component	cytosol Traceable author statement. Source: Reactome death-inducing signaling complex Inferred from direct assay Ref.14. Source: BHF-UCL endosome membrane Traceable author statement. Source: Reactome membrane raft Inferred from electronic annotation. Source: Compara mitochondrion Inferred from direct assay PubMed 16507998. Source: BHF-UCL receptor complex Inferred from direct assay Ref.1. Source: BHF-UCL
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein serine/threonine kinase activity Inferred from direct assay Ref.1. Source: BHF-UCL
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		5	EBI-358507,EBI-358507
ANXA1	P04083	5	EBI-358507,EBI-354007
BIRC2	Q13490	3	EBI-358507,EBI-514538
BIRC3	Q13489	3	EBI-358507,EBI-517709
CASP10	Q92851	2	EBI-358507,EBI-495095
CASP8	Q14790	23	EBI-358507,EBI-78060
CCDC50	Q8IVM0	2	EBI-358507,EBI-723996
CSNK1A1	P48729	5	EBI-358507,EBI-1383726
FADD	Q13158	5	EBI-358507,EBI-494804
IKBKG	Q9Y6K9	6	EBI-358507,EBI-81279
RIPK3	Q9Y572	24	EBI-358507,EBI-298250
TNFRSF1A	P19438	6	EBI-358507,EBI-299451

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q13546-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q13546-2)

The sequence of this isoform differs from the canonical sequence as follows:
     108-153: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 671	671	Receptor-interacting serine/threonine-protein kinase 1		PRO_0000086606
Regions
	Domain	17 – 289	273	Protein kinase
	Domain	583 – 669	87	Death
	Nucleotide binding	23 – 31	9	ATP By similarity
	Region	290 – 582	293	Interaction with SQSTM1
	Motif	531 – 547	17	RIP homotypic interaction motif (RHIM)
	Compositional bias	411 – 414	4	Poly-Arg
Sites
	Active site	138	1	Proton acceptor By similarity
	Binding site	49	1	ATP By similarity
	Site	324 – 325	2	Cleavage; by caspase-8
Amino acid modifications
	Modified residue	6	1	Phosphoserine Ref.25
	Modified residue	20	1	Phosphoserine; by autocatalysis Potential
	Modified residue	25	1	Phosphoserine Ref.25
	Modified residue	161	1	Phosphoserine; by RIPK3 and autocatalysis Potential
	Modified residue	166	1	Phosphoserine; by autocatalysis Potential
	Modified residue	303	1	Phosphoserine Ref.25
	Modified residue	320	1	Phosphoserine Ref.25 Ref.27
	Modified residue	333	1	Phosphoserine Ref.25
	Modified residue	384	1	Phosphotyrosine Ref.18
	Cross-link	377		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Natural variations
	Alternative sequence	108 – 153	46	Missing in isoform 2.		VSP_037690
	Natural variant	64	1	A → V in a colorectal adenocarcinoma sample; somatic mutation. Ref.35		VAR_041039
	Natural variant	81	1	V → I in a colorectal adenocarcinoma sample; somatic mutation. Ref.35		VAR_041040
	Natural variant	220	1	A → V in a colorectal adenocarcinoma sample; somatic mutation. Ref.35		VAR_041041
	Natural variant	234	1	E → K. Ref.4 Corresponds to variant rs17548383 [ dbSNP | Ensembl ].		VAR_021109
	Natural variant	404	1	A → S. Ref.35 Corresponds to variant rs34872409 [ dbSNP | Ensembl ].		VAR_041042
	Natural variant	438	1	A → V. Ref.1 Ref.6 Ref.8 Corresponds to variant rs3173519 [ dbSNP | Ensembl ].		VAR_058285
	Natural variant	443	1	A → V. Ref.35 Corresponds to variant rs35722193 [ dbSNP | Ensembl ].		VAR_041043
	Natural variant	569	1	A → V. Ref.35 Corresponds to variant rs55861377 [ dbSNP | Ensembl ].		VAR_041044
Experimental info
	Mutagenesis	45	1	K → A: Abolishes kinase activity. Ref.1
	Mutagenesis	161	1	S → A: Decreases RIPK1 kinase activity. Ref.25
	Mutagenesis	161	1	S → E: No effect on RIPK1 autophosphorylation. Ref.25
	Mutagenesis	324	1	D → K: Abolishes cleavage by caspase-8. Ref.9
	Mutagenesis	377	1	K → R: Abolishes RIP-mediated NF-Kappa-B activation. Ref.22
	Sequence conflict	258	1	R → I in BAG36858. Ref.3
	Sequence conflict	286	1	R → S in BAG36858. Ref.3
	Sequence conflict	514	1	T → S in AAC50137. Ref.8

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 1, 2005. Version 3. Checksum: 976E2428D525A9B2	FASTA	671	75,931
	10 20 30 40 50 60 MQPDMSLNVI KMKSSDFLES AELDSGGFGK VSLCFHRTQG LMIMKTVYKG PNCIEHNEAL 70 80 90 100 110 120 LEEAKMMNRL RHSRVVKLLG VIIEEGKYSL VMEYMEKGNL MHVLKAEMST PLSVKGRIIL 130 140 150 160 170 180 EIIEGMCYLH GKGVIHKDLK PENILVDNDF HIKIADLGLA SFKMWSKLNN EEHNELREVD 190 200 210 220 230 240 GTAKKNGGTL YYMAPEHLND VNAKPTEKSD VYSFAVVLWA IFANKEPYEN AICEQQLIMC 250 260 270 280 290 300 IKSGNRPDVD DITEYCPREI ISLMKLCWEA NPEARPTFPG IEEKFRPFYL SQLEESVEED 310 320 330 340 350 360 VKSLKKEYSN ENAVVKRMQS LQLDCVAVPS SRSNSATEQP GSLHSSQGLG MGPVEESWFA 370 380 390 400 410 420 PSLEHPQEEN EPSLQSKLQD EANYHLYGSR MDRQTKQQPR QNVAYNREEE RRRRVSHDPF 430 440 450 460 470 480 AQQRPYENFQ NTEGKGTAYS SAASHGNAVH QPSGLTSQPQ VLYQNNGLYS SHGFGTRPLD 490 500 510 520 530 540 PGTAGPRVWY RPIPSHMPSL HNIPVPETNY LGNTPTMPFS SLPPTDESIK YTIYNSTGIQ 550 560 570 580 590 600 IGAYNYMEIG GTSSSLLDST NTNFKEEPAA KYQAIFDNTT SLTDKHLDPI RENLGKHWKN 610 620 630 640 650 660 CARKLGFTQS QIDEIDHDYE RDGLKEKVYQ MLQKWVMREG IKGATVGKLA QALHQCSRID 670 LLSSLIYVSQ N
	Isoform 2 [UniParc]. Checksum: 4D3780FB4A93FDB1	FASTA	625	70,733
	10 20 30 40 50 60 MQPDMSLNVI KMKSSDFLES AELDSGGFGK VSLCFHRTQG LMIMKTVYKG PNCIEHNEAL 70 80 90 100 110 120 LEEAKMMNRL RHSRVVKLLG VIIEEGKYSL VMEYMEKGNL MHVLKAEIAD LGLASFKMWS 130 140 150 160 170 180 KLNNEEHNEL REVDGTAKKN GGTLYYMAPE HLNDVNAKPT EKSDVYSFAV VLWAIFANKE 190 200 210 220 230 240 PYENAICEQQ LIMCIKSGNR PDVDDITEYC PREIISLMKL CWEANPEARP TFPGIEEKFR 250 260 270 280 290 300 PFYLSQLEES VEEDVKSLKK EYSNENAVVK RMQSLQLDCV AVPSSRSNSA TEQPGSLHSS 310 320 330 340 350 360 QGLGMGPVEE SWFAPSLEHP QEENEPSLQS KLQDEANYHL YGSRMDRQTK QQPRQNVAYN 370 380 390 400 410 420 REEERRRRVS HDPFAQQRPY ENFQNTEGKG TAYSSAASHG NAVHQPSGLT SQPQVLYQNN 430 440 450 460 470 480 GLYSSHGFGT RPLDPGTAGP RVWYRPIPSH MPSLHNIPVP ETNYLGNTPT MPFSSLPPTD 490 500 510 520 530 540 ESIKYTIYNS TGIQIGAYNY MEIGGTSSSL LDSTNTNFKE EPAAKYQAIF DNTTSLTDKH 550 560 570 580 590 600 LDPIRENLGK HWKNCARKLG FTQSQIDEID HDYERDGLKE KVYQMLQKWV MREGIKGATV 610 620 GKLAQALHQC SRIDLLSSLI YVSQN

References

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[1]	"TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex." Hsu H., Huang J., Shu H.-B., Baichwal V.R., Goeddel D.V. Immunity 4:387-396(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AUTOPHOSPHORYLATION, MUTAGENESIS OF LYS-45, INTERACTION WITH TRADD; TRAF1; TRAF2 AND TRAF3, VARIANT VAL-438. Tissue: Umbilical vein endothelial cell.
[2]	Huang J., Hsu H., Baichwal V.R., Goeddel D.V. Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION TO 120.
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." 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 T.-O., 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. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 15-671 (ISOFORM 2). Tissue: Adrenal gland and Uterus.
[4]	SeattleSNPs variation discovery resource Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT LYS-234.
[5]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT VAL-438.
[7]	"Homo sapiens protein coding cDNA." Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., Ohara O., Nagase T., Kikuno R.F. Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 153-671. Tissue: Brain.
[8]	"RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death." Stanger B.Z., Leder P., Lee T.-H., Kim E., Seed B. Cell 81:513-523(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 300-671, VARIANT VAL-438. Tissue: Leukemic T-cell.
[9]	"Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis." Lin Y., Devin A., Rodriguez Y., Liu Z.-G. Genes Dev. 13:2514-2526(1999) [PubMed] [Europe PMC] [Abstract] Cited for: CLEAVAGE BY CASPASE-8, MUTAGENESIS OF ASP-324.
[10]	"The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation." Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J. EMBO J. 18:3044-3053(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SQSTM1 AND TRAF2, DOMAIN.
[11]	"RIP3, a novel apoptosis-inducing kinase." Sun X., Lee J., Navas T., Baldwin D.T., Stewart T.A., Dixit V.M. J. Biol. Chem. 274:16871-16875(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH RIPK3.
[12]	"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." Izumi K.M., Cahir McFarland E., Ting A.T., Riley E.A., Seed B., Kieff E.D. Mol. Cell. Biol. 19:5759-5767(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH BNLF1.
[13]	"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." Li Y., Kang J., Friedman J., Tarassishin L., Ye J., Kovalenko A., Wallach D., Horwitz M.S. Proc. Natl. Acad. Sci. U.S.A. 96:1042-1047(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH IKBKG.
[14]	"Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule." Holler N., Zaru R., Micheau O., Thome M., Attinger A., Valitutti S., Bodmer J.L., Schneider P., Seed B., Tschopp J. Nat. Immunol. 1:489-495(2000) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[15]	"The epidermal growth factor receptor engages receptor interacting protein and nuclear factor-kappa B (NF-kappa B)-inducing kinase to activate NF-kappa B. Identification of a novel receptor-tyrosine kinase signalosome." Habib A.A., Chatterjee S., Park S.-K., Ratan R.R., Lefebvre S., Vartanian T. J. Biol. Chem. 276:8865-8874(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH EGFR.
[16]	"A novel zinc finger protein interacts with receptor-interacting protein (RIP) and inhibits tumor necrosis factor (TNF)- and IL1-induced NF-kappa B activation." Chen D., Li X., Zhai Z., Shu H.-B. J. Biol. Chem. 277:15985-15991(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH RNF216.
[17]	"Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3." Sun X., Yin J., Starovasnik M.A., Fairbrother W.J., Dixit V.M. J. Biol. Chem. 277:9505-9511(2002) [PubMed] [Europe PMC] [Abstract] Cited for: RIP HOMOTYPIC INTERACTION MOTIF, INTERACTION WITH RIPK3.
[18]	"Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry." Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., Peters E.C. Anal. Chem. 76:2763-2772(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-384, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[19]	"ZNF216 is an A20-like and IkappaB kinase gamma-interacting inhibitor of NFkappaB activation." Huang J., Teng L., Li L., Liu T., Li L., Chen D., Xu L.-G., Zhai Z., Shu H.-B. J. Biol. Chem. 279:16847-16853(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ZFAND5.
[20]	"De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling." Wertz I.E., O'Rourke K.M., Zhou H., Eby M., Aravind L., Seshagiri S., Wu P., Wiesmann C., Baker R., Boone D.L., Ma A., Koonin E.V., Dixit V.M. Nature 430:694-699(2004) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION BY TRAF2, DEUBIQUITINATION BY TNFAIP3.
[21]	"IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction." Kawai T., Takahashi K., Sato S., Coban C., Kumar H., Kato H., Ishii K.J., Takeuchi O., Akira S. Nat. Immunol. 6:981-988(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MAVS.
[22]	"Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO." Ea C.K., Deng L., Xia Z.P., Pineda G., Chen Z.J. Mol. Cell 22:245-257(2006) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION AT LYS-377, MUTAGENESIS OF LYS-377.
[23]	"RIP1, a kinase on the crossroads of a cell's decision to live or die." Festjens N., Vanden Berghe T., Cornelis S., Vandenabeele P. Cell Death Differ. 14:400-410(2007) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[24]	"RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-triggered NF-kappaB activation by targeting TAB2/3 for degradation." Tian Y., Zhang Y., Zhong B., Wang Y.Y., Diao F.C., Wang R.P., Zhang M., Chen D.Y., Zhai Z.H., Shu H.B. J. Biol. Chem. 282:16776-16782(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH RBCK1.
[25]	"Identification of RIP1 kinase as a specific cellular target of necrostatins." Degterev A., Hitomi J., Germscheid M., Ch'en I.L., Korkina O., Teng X., Abbott D., Cuny G.D., Yuan C., Wagner G., Hedrick S.M., Gerber S.A., Lugovskoy A., Yuan J. Nat. Chem. Biol. 4:313-321(2008) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF SER-161, INHIBITION BY NECROSTATIN-1, PHOSPHORYLATION AT SER-6; SER-20; SER-25; SER-161; SER-166; SER-303; SER-320 AND SER-333.
[26]	"Cytomegalovirus M45 cell death suppression requires receptor-interacting protein (RIP) homotypic interaction motif (RHIM)-dependent interaction with RIP1." Upton J.W., Kaiser W.J., Mocarski E.S. J. Biol. Chem. 283:16966-16970(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MURID HERPESVIRUS 1 VIRAL INHIBITOR OF RIP ACTIVATION.
[27]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[28]	"Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation." Cho Y.S., Challa S., Moquin D., Genga R., Ray T.D., Guildford M., Chan F.K. Cell 137:1112-1123(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION.
[29]	"Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha." He S., Wang L., Miao L., Wang T., Du F., Zhao L., Wang X. Cell 137:1100-1111(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH RIPK3.
[30]	"The role of the kinases RIP1 and RIP3 in TNF-induced necrosis." Vandenabeele P., Declercq W., Van Herreweghe F., Vanden Berghe T. Sci. Signal. 3:RE4-RE4(2010) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[31]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[32]	"Linear ubiquitination prevents inflammation and regulates immune signalling." Gerlach B., Cordier S.M., Schmukle A.C., Emmerich C.H., Rieser E., Haas T.L., Webb A.I., Rickard J.A., Anderton H., Wong W.W., Nachbur U., Gangoda L., Warnken U., Purcell A.W., Silke J., Walczak H. Nature 471:591-596(2011) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION BY THE LUBAC COMPLEX.
[33]	"cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4)." Bertrand M.J., Lippens S., Staes A., Gilbert B., Roelandt R., De Medts J., Gevaert K., Declercq W., Vandenabeele P. PLoS ONE 6:E22356-E22356(2011) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION BY BIRC2/C-IAP1 AND BIRC3/C-IAP2, INTERACTION WITH BIRC2/C-IAP1; BIRC3/C-IAP2 AND XIAP/BIRC4.
[34]	"The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways." Wang Z., Jiang H., Chen S., Du F., Wang X. Cell 148:228-243(2012) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN COMPLEX WITH PGAM5; RIPK3 AND MLKL.
[35]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] VAL-64; ILE-81; VAL-220; SER-404; VAL-443 AND VAL-569.
+	Additional computationally mapped references.

Web resources

SeattleSNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U50062 mRNA. Translation: AAC32232.1.
AK314176 mRNA. Translation: BAG36858.1.
AK304701 mRNA. Translation: BAG65471.1. Different initiation.
AY682848 Genomic DNA. Translation: AAT74626.1.
AL031963 Genomic DNA. Translation: CAD70625.1.
BC126254 mRNA. Translation: AAI26255.1.
BC126256 mRNA. Translation: AAI26257.1.
AB208926 mRNA. Translation: BAD92163.1.
U25994 mRNA. Translation: AAC50137.1.

IPI

IPI00013773.
IPI00939198.

PIR

T09479.

RefSeq

NP_003795.2. NM_003804.3.

UniGene

Hs.519842.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
4ITH	X-ray	2.25	A/B	1-294	[»]
4ITI	X-ray	2.86	A/B	1-294	[»]
4ITJ	X-ray	1.80	A/B	1-294	[»]

ProteinModelPortal

Q13546.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-433N.

IntAct

Q13546. 28 interactions.

MINT

MINT-128219.

STRING

9606.ENSP00000259808.

PTM databases

PhosphoSite

Q13546.

Polymorphism databases

DMDM

60393639.

Proteomic databases

PaxDb

Q13546.

PRIDE

Q13546.

Protocols and materials databases

DNASU

8737.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000259808; ENSP00000259808; ENSG00000137275.
ENST00000380409; ENSP00000369773; ENSG00000137275.
ENST00000541791; ENSP00000442294; ENSG00000137275.

GeneID

8737.

KEGG

hsa:8737.

UCSC

uc003muv.4. human.
uc011dhs.2. human.

Organism-specific databases

CTD

8737.

GeneCards

GC06P003064.

HGNC

HGNC:10019. RIPK1.

HPA

CAB010302.
HPA015257.

MIM

603453. gene.

neXtProt

NX_Q13546.

PharmGKB

PA34394.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000010270.

HOVERGEN

HBG055612.

InParanoid

Q13546.

KO

K02861.

OMA

SHDPFAQ.

OrthoDB

EOG434W5G.

PhylomeDB

Q13546.

Enzyme and pathway databases

BRENDA

2.7.10.2. 2681.

Pathway_Interaction_DB

caspase_pathway. Caspase cascade in apoptosis.
ceramidepathway. Ceramide signaling pathway.
faspathway. FAS signaling pathway (CD95).
hivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha.
p38alphabetapathway. Regulation of p38-alpha and p38-beta.
tnfpathway. TNF receptor signaling pathway.
trail_pathway. TRAIL signaling pathway.

Reactome

REACT_578. Apoptosis.
REACT_6900. Immune System.

Gene expression databases

Bgee

Q13546.

CleanEx

HS_RIPK1.

Genevestigator

Q13546.

Family and domain databases

Gene3D

1.10.533.10. 1 hit.

InterPro

IPR011029. DEATH-like_dom.
IPR000488. Death_domain.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR025735. RHIM_dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

PF00531. Death. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF12721. RHIM. 1 hit.
[Graphical view]

PRINTS

PR00109. TYRKINASE.

SMART

SM00005. DEATH. 1 hit.
[Graphical view]

SUPFAM

SSF47986. DEATH_like. 1 hit.
SSF56112. Kinase_like. 1 hit.

PROSITE

PS50017. DEATH_DOMAIN. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q13546.

ChEMBL

CHEMBL5464.

GenomeRNAi

8737.

NextBio

32775.

PMAP-CutDB

Q13546.

SOURCE

Search...

Entry information

Entry name

RIPK1_HUMAN

Accession

Primary (citable) accession number: Q13546
Secondary accession number(s): A0AV89 , B2RAG1, B4E3F9, Q13180, Q59H33

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	February 1, 2005
Last modified:	May 1, 2013
This is version 142 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.