RIPK1 (receptor interacting serine/threonine kinase 1)

Gene

• Entrez ID: 8737
• Gene name: Receptor interacting serine/threonine kinase 1
• Gene symbol: RIPK1
• Synonyms: AIEFL, IMD57, RIP, RIP-1, RIP1
• Chromosome: 6
• Chromosome location: 6p25.2
• Summary: This gene encodes a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. The encoded protein plays a role in inflammation and cell death in response to tissue damage, pathogen recognition, and as part of developmental regulation. RIPK1/RIPK3 kinase-mediated necrosis is referred to as necroptosis. Genetic disruption of this gene in mice results in death shortly after birth. [provided by RefSeq, Aug 2017]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs1561772403	G>-	Pathogenic, likely-pathogenic	Genic downstream transcript variant, coding sequence variant, frameshift variant

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0001934	Process	Positive regulation of protein phosphorylation	IMP	17389591
GO:0002756	Process	MyD88-independent toll-like receptor signaling pathway	TAS
GO:0004672	Function	Protein kinase activity	IBA	21873635
GO:0004672	Function	Protein kinase activity	IDA	15001576, 22265413
GO:0004672	Function	Protein kinase activity	IMP	22817896
GO:0004674	Function	Protein serine/threonine kinase activity	IDA	8612133, 23473668
GO:0004674	Function	Protein serine/threonine kinase activity	IMP	30988283, 31827280
GO:0004706	Function	JUN kinase kinase kinase activity	IBA	21873635
GO:0005123	Function	Death receptor binding	IPI	7538908
GO:0005515	Function	Protein binding	IPI	10356400, 12884866, 12887920, 14653779, 16127453, 16611992, 17047155, 17389591, 17449468, 18022363, 18029035, 18067272, 18485876, 19060883, 19524512, 19524513, 19781631, 21383699, 21458669, 21525013, 21810480, 21887730, 21931591, 22173242, 22265413, 22265414, 22274400, 22817896, 231
GO:0005524	Function	ATP binding	IEA
GO:0005739	Component	Mitochondrion	IDA	16507998
GO:0005829	Component	Cytosol	IDA
GO:0005829	Component	Cytosol	TAS
GO:0005886	Component	Plasma membrane	IDA
GO:0006915	Process	Apoptotic process	IMP	21737330, 22891283, 29440439
GO:0006919	Process	Activation of cysteine-type endopeptidase activity involved in apoptotic process	TAS
GO:0006954	Process	Inflammatory response	IEA
GO:0007249	Process	I-kappaB kinase/NF-kappaB signaling	TAS
GO:0007256	Process	Activation of JNKK activity	IEA
GO:0007257	Process	Activation of JUN kinase activity	IBA	21873635
GO:0007257	Process	Activation of JUN kinase activity	TAS	17979836
GO:0008219	Process	Cell death	IMP	30988283
GO:0010008	Component	Endosome membrane	TAS
GO:0010803	Process	Regulation of tumor necrosis factor-mediated signaling pathway	TAS
GO:0010940	Process	Positive regulation of necrotic cell death	IMP	20550618
GO:0016032	Process	Viral process	IEA
GO:0016579	Process	Protein deubiquitination	TAS
GO:0031264	Component	Death-inducing signaling complex	IDA	11101870
GO:0031625	Function	Ubiquitin protein ligase binding	IPI	18450452
GO:0032757	Process	Positive regulation of interleukin-8 production	IDA	16127453
GO:0032760	Process	Positive regulation of tumor necrosis factor production	IDA	16127453
GO:0032991	Component	Protein-containing complex	IDA	22817896
GO:0033209	Process	Tumor necrosis factor-mediated signaling pathway	IC	8612133
GO:0033209	Process	Tumor necrosis factor-mediated signaling pathway	TAS
GO:0034138	Process	Toll-like receptor 3 signaling pathway	TAS
GO:0034612	Process	Response to tumor necrosis factor	IMP	10521396
GO:0035666	Process	TRIF-dependent toll-like receptor signaling pathway	TAS
GO:0036289	Process	Peptidyl-serine autophosphorylation	IDA	23473668
GO:0036289	Process	Peptidyl-serine autophosphorylation	IMP	31827280
GO:0042802	Function	Identical protein binding	IPI	22817896, 23473668, 25416956, 32296183
GO:0042803	Function	Protein homodimerization activity	IDA	29440439
GO:0043065	Process	Positive regulation of apoptotic process	IDA	8612133, 17389591
GO:0043065	Process	Positive regulation of apoptotic process	IMP	22173242
GO:0043066	Process	Negative regulation of apoptotic process	ISS
GO:0043068	Process	Positive regulation of programmed cell death	IMP	16611992
GO:0043123	Process	Positive regulation of I-kappaB kinase/NF-kappaB signaling	IDA	17389591
GO:0043123	Process	Positive regulation of I-kappaB kinase/NF-kappaB signaling	IEP	12761501
GO:0043124	Process	Negative regulation of I-kappaB kinase/NF-kappaB signaling	IMP	17047155
GO:0043235	Component	Receptor complex	IDA	8612133
GO:0044257	Process	Cellular protein catabolic process	IDA	17389591
GO:0044877	Function	Protein-containing complex binding	IDA	22265414
GO:0045121	Component	Membrane raft	IEA
GO:0045651	Process	Positive regulation of macrophage differentiation	IMP	17047155
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IDA	16127453, 17389591
GO:0046330	Process	Positive regulation of JNK cascade	IDA	17389591
GO:0046777	Process	Protein autophosphorylation	IDA	8612133
GO:0046777	Process	Protein autophosphorylation	IMP	29440439
GO:0050729	Process	Positive regulation of inflammatory response	IMP	31827280
GO:0051092	Process	Positive regulation of NF-kappaB transcription factor activity	IMP	8612133, 10521396, 21931591
GO:0060545	Process	Positive regulation of necroptotic process	IMP	22028622, 22274400, 22817896
GO:0060546	Process	Negative regulation of necroptotic process	ISS
GO:0070105	Process	Positive regulation of interleukin-6-mediated signaling pathway	IMP	31827280
GO:0070231	Process	T cell apoptotic process	ISS
GO:0070266	Process	Necroptotic process	IMP	21737330, 22265414, 29440439
GO:0070266	Process	Necroptotic process	ISS
GO:0070266	Process	Necroptotic process	TAS
GO:0070301	Process	Cellular response to hydrogen peroxide	ISS
GO:0070513	Function	Death domain binding	IPI	8612133, 9044836
GO:0070926	Process	Regulation of ATP:ADP antiporter activity	IMP	16507998
GO:0071356	Process	Cellular response to tumor necrosis factor	IDA	17389591
GO:0071550	Process	Death-inducing signaling complex assembly	TAS
GO:0097190	Process	Apoptotic signaling pathway	TAS
GO:0097191	Process	Extrinsic apoptotic signaling pathway	IDA	7538908
GO:0097191	Process	Extrinsic apoptotic signaling pathway	IMP	8612133, 10521396
GO:0097300	Process	Programmed necrotic cell death	ISS
GO:0097342	Component	Ripoptosome	IDA	21737330
GO:0097343	Process	Ripoptosome assembly	IMP	21737330
GO:0097527	Process	Necroptotic signaling pathway	IMP	11101870, 16507998, 22265413, 22817896, 31827280
GO:0097527	Process	Necroptotic signaling pathway	ISS
GO:0106310	Function	Protein serine kinase activity	IEA
GO:0106311	Function	Protein threonine kinase activity	IEA
GO:1902041	Process	Regulation of extrinsic apoptotic signaling pathway via death domain receptors	TAS
GO:1902042	Process	Negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	TAS
GO:1903800	Process	Positive regulation of production of miRNAs involved in gene silencing by miRNA	IDA	26020802
GO:1905206	Process	Positive regulation of hydrogen peroxide-induced cell death	IMP	20550618
GO:1990000	Process	Amyloid fibril formation	IMP	22817896
GO:2000379	Process	Positive regulation of reactive oxygen species metabolic process	TAS	17979836
GO:2001237	Process	Negative regulation of extrinsic apoptotic signaling pathway	IMP	21525013
GO:2001238	Process	Positive regulation of extrinsic apoptotic signaling pathway	IMP	21525013, 22274400

Other IDs

• MIM: 603453
• HGNC: 10019
• e!Ensembl: ENSG00000137275

Protein

• UniProt ID: Q13546
• Protein name: Receptor-interacting serine/threonine-protein kinase 1 (EC 2.7.11.1) (Cell death protein RIP) (Receptor-interacting protein 1) (RIP-1)
• Protein function: Serine-threonine kinase which is a key regulator of TNF-mediated apoptosis, necroptosis and inflammatory pathways (PubMed:31827280, PubMed:31827281). Exhibits kinase activity-dependent functions that regulate cell death and kinase-independent scaffold functions regulating inflammatory signaling and cell survival (PubMed:11101870, PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). Has kinase-independent scaffold functions: upon binding of TNF to TNFR1, RIPK1 is recruited to the TNF-R1 signaling complex (TNF-RSC also known as complex I) where it acts as a scaffold protein promoting cell survival, in part, by activating the canonical NF-kappa-B pathway (By similarity). Kinase activity is essential to regulate necroptosis and apoptosis, two parallel forms of cell death: upon activation of its protein kinase activity, regulates assembly of two death-inducing complexes, namely complex IIa (RIPK1-FADD-CASP8), which drives apoptosis, and the complex IIb (RIPK1-RIPK3-MLKL), which drives necroptosis (By similarity). RIPK1 is required to limit CASP8-dependent TNFR1-induced apoptosis (By similarity). In normal conditions, RIPK1 acts as an inhibitor of RIPK3-dependent necroptosis, a process mediated by RIPK3 component of complex IIb, which catalyzes phosphorylation of MLKL upon induction by ZBP1 (PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). Inhibits RIPK3-mediated necroptosis via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis (PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). Required to inhibit apoptosis and necroptosis during embryonic development: acts by preventing the interaction of TRADD with FADD thereby limiting aberrant activation of CASP8 (By similarity). In addition to apoptosis and necroptosis, also involved in inflammatory response by promoting transcriptional production of pro-inflammatory cytokines, such as interleukin-6 (IL6) (PubMed:31827280, PubMed:31827281). Phosphorylates RIPK3: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (PubMed:19524513). Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade (PubMed:17389591, PubMed:15310755). Required for ZBP1-induced NF-kappa-B activation in response to DNA damage (By similarity).
• PDB: 4ITH, 4ITI, 4ITJ, 4NEU, 5HX6, 5TX5, 5V7Z, 6AC5, 6C3E, 6C4D, 6HHO, 6NW2, 6NYH, 6OCQ, 6R5F, 6RLN
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF07714	PK_Tyr_Ser-Thr	18 → 285	Protein tyrosine and serine/threonine kinase	Domain
  PF12721	RHIM	504 → 549	RIP homotypic interaction motif	Family
  PF00531	Death	584 → 669	Death domain	Domain

• Sequence:

  MQPDMSLNVIKMKSSDFLESAELDSGGFGKVSLCFHRTQGLMIMKTVYKGPNCIEHNEAL
  LEEAKMMNRLRHSRVVKLLGVIIEEGKYSLVMEYMEKGNLMHVLKAEMSTPLSVKGRIIL
  EIIEGMCYLHGKGVIHKDLKPENILVDNDFHIKIADLGLASFKMWSKLNNEEHNELREVD
  GTAKKNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMC
  IKSGNRPDVDDITEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPFYLSQLEESVEED
  VKSLKKEYSNENAVVKRMQSLQLDCVAVPSSRSNSATEQPGSLHSSQGLGMGPVEESWFA
  PSLEHPQEENEPSLQSKLQDEANYHLYGSRMDRQTKQQPRQNVAYNREEERRRRVSHDPF
  AQQRPYENFQNTEGKGTAYSSAASHGNAVHQPSGLTSQPQVLYQNNGLYSSHGFGTRPLD
  PGTAGPRVWYRPIPSHMPSLHNIPVPETNYLGNTPTMPFSSLPPTDESIKYTIYNSTGIQ
  IGAYNYMEIGGTSSSLLDSTNTNFKEEPAAKYQAIFDNTTSLTDKHLDPIRENLGKHWKN
  CARKLGFTQSQIDEIDHDYERDGLKEKVYQMLQKWVMREGIKGATVGKLAQALHQCSRID
  LLSSLIYVSQN

• Sequence length: 671