ID:RIPK1_HUMAN DESCRIPTION: RecName: Full=Receptor-interacting serine/threonine-protein kinase 1; EC=2.7.11.1; AltName: Full=Cell death protein RIP; AltName: Full=Receptor-interacting protein 1; Short=RIP-1; AltName: Full=Serine/threonine-protein kinase RIP; FUNCTION: Serine-threonine kinase which transduces inflammatory and cell-death signals (necroptosis) 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 necroptosis-inducing complex. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: Inhibited by necrostatin-1. SUBUNIT: Interacts (via RIP homotypic interaction motif) with RIPK3 (via RIP homotypic interaction motif); this interaction induces RIPK1 necroptosis-specific phosphorylation, formation of the necroptosis-inducing complex. 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. INTERACTION: Self; NbExp=5; IntAct=EBI-358507, EBI-358507; P04083:ANXA1; NbExp=5; IntAct=EBI-358507, EBI-354007; Q13490:BIRC2; NbExp=3; IntAct=EBI-358507, EBI-514538; Q13489:BIRC3; NbExp=3; IntAct=EBI-358507, EBI-517709; Q92851:CASP10; NbExp=2; IntAct=EBI-358507, EBI-495095; Q14790:CASP8; NbExp=23; IntAct=EBI-358507, EBI-78060; Q8IVM0:CCDC50; NbExp=2; IntAct=EBI-358507, EBI-723996; P48729:CSNK1A1; NbExp=5; IntAct=EBI-358507, EBI-1383726; Q13158:FADD; NbExp=5; IntAct=EBI-358507, EBI-494804; Q9Y6K9:IKBKG; NbExp=6; IntAct=EBI-358507, EBI-81279; Q9Y572:RIPK3; NbExp=24; IntAct=EBI-358507, EBI-298250; P19438:TNFRSF1A; NbExp=6; IntAct=EBI-358507, EBI-299451; 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. PTM: 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. PTM: 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. PTM: 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. SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. SIMILARITY: Contains 1 death domain. SIMILARITY: Contains 1 protein kinase domain. SEQUENCE CAUTION: Sequence=BAG65471.1; Type=Erroneous initiation; WEB RESOURCE: Name=SeattleSNPs; URL="http://pga.gs.washington.edu/data/ripk1/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00069 - Protein kinase domain PF00531 - Death domain PF07714 - Protein tyrosine and serine/threonine kinase PF12721 - RIP homotypic interaction motif
SCOP Domains: 47986 - DEATH domain 56112 - Protein kinase-like (PK-like)
ModBase Predicted Comparative 3D Structure on Q13546
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0001934 positive regulation of protein phosphorylation GO:0002756 MyD88-independent toll-like receptor signaling pathway GO:0006468 protein phosphorylation GO:0006915 apoptotic process GO:0006919 activation of cysteine-type endopeptidase activity involved in apoptotic process GO:0007165 signal transduction GO:0007249 I-kappaB kinase/NF-kappaB signaling GO:0007257 activation of JUN kinase activity GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway GO:0010940 positive regulation of necrotic cell death GO:0010942 positive regulation of cell death GO:0012501 programmed cell death GO:0016032 viral process GO:0016310 phosphorylation GO:0016579 protein deubiquitination GO:0032757 positive regulation of interleukin-8 production GO:0032760 positive regulation of tumor necrosis factor production GO:0033209 tumor necrosis factor-mediated signaling pathway GO:0034138 toll-like receptor 3 signaling pathway GO:0034612 response to tumor necrosis factor GO:0035666 TRIF-dependent toll-like receptor signaling pathway GO:0036289 peptidyl-serine autophosphorylation GO:0042327 positive regulation of phosphorylation GO:0043065 positive regulation of apoptotic process GO:0043068 positive regulation of programmed cell death GO:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling GO:0043124 negative regulation of I-kappaB kinase/NF-kappaB signaling GO:0043410 positive regulation of MAPK cascade GO:0044257 cellular protein catabolic process GO:0045651 positive regulation of macrophage differentiation GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0046330 positive regulation of JNK cascade GO:0046777 protein autophosphorylation GO:0051092 positive regulation of NF-kappaB transcription factor activity GO:0051260 protein homooligomerization GO:0051291 protein heterooligomerization GO:0060545 positive regulation of necroptotic process GO:0070231 T cell apoptotic process GO:0070266 necroptotic process GO:0070926 regulation of ATP:ADP antiporter activity GO:0071356 cellular response to tumor necrosis factor GO:0071363 cellular response to growth factor stimulus GO:0071550 death-inducing signaling complex assembly GO:0097190 apoptotic signaling pathway GO:0097191 extrinsic apoptotic signaling pathway GO:0097343 ripoptosome assembly GO:0097527 necroptotic signaling pathway GO:1901026 ripoptosome assembly involved in necroptotic process GO:1902041 regulation of extrinsic apoptotic signaling pathway via death domain receptors GO:1902042 negative regulation of extrinsic apoptotic signaling pathway via death domain receptors GO:1905206 positive regulation of hydrogen peroxide-induced cell death GO:1990000 amyloid fibril formation GO:2000377 regulation of reactive oxygen species metabolic process GO:2000379 positive regulation of reactive oxygen species metabolic process GO:2001237 negative regulation of extrinsic apoptotic signaling pathway GO:2001238 positive regulation of extrinsic apoptotic signaling pathway GO:2001240 negative regulation of extrinsic apoptotic signaling pathway in absence of ligand
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
