Protein: Receptor-interacting serine/threonine-protein kinase 1 (EC 2.7.11.1) (Cell death protein RIP) (Receptor-interacting protein 1) (RIP-1) (Q60855)
Organism: Mus musculus (Mouse)
Function: Serine-threonine kinase which is a key regulator of TNF-mediated apoptosis, necroptosis and inflammatory pathways. Exhibits kinase activity-dependent functions that regulate cell death and kinase-independent scaffold functions regulating inflammatory signaling and cell survival. 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. 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. RIPK1 is required to limit CASP8-dependent TNFR1-induced apoptosis. 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. Inhibits RIPK3-mediated necroptosis via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis. Required to inhibit apoptosis and necroptosis during embryonic development: acts by preventing the interaction of TRADD with FADD thereby limiting aberrant activation of CASP8. In addition to apoptosis and necroptosis, also involved in inflammatory response by promoting transcriptional production of pro-inflammatory cytokines, such as interleukin-6 (IL6). Phosphorylates RIPK3: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (By similarity). Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade (By similarity). Required for ZBP1-induced NF-kappa-B activation in response to DNA damage.
Subcellular location: Cytoplasm {ECO:0000269|PubMed:23283962, ECO:0000269|PubMed:7538908}. Cell membrane {ECO:0000250|UniProtKB:Q9ZUF4}.
Sequence: MQPDMSLDNIKMASSDLLEKTDLDSGGFGKVSLCYHRSHGFVILKKVYTGPNRAEYNEVLLEEGKMMHRLRHSRVVKLLGIIIEEGNYSLVMEYMEKGNLMHVLKTQIDVPLSLKGRIIVEAIEGMCYLHDKGVIHKDLKPENILVDRDFHIKIADLGVASFKTWSKLTKEKDNKQKEVSSTTKKNNGGTLYYMAPEHLNDINAKPTEKSDVYSFGIVLWAIFAKKEPYENVICTEQFVICIKSGNRPNVEEILEYCPREIISLMERCWQAIPEDRPTFLGIEEEFRPFYLSHFEEYVEEDVASLKKEYPDQSPVLQRMFSLQHDCVPLPPSRSNSEQPGSLHSSQGLQMGPVEESWFSSSPEYPQDENDRSVQAKLQEEASYHAFGIFAEKQTKPQPRQNEAYNREEERKRRVSHDPFAQQRARENIKSAGARGHSDPSTTSRGIAVQQLSWPATQTVWNNGLYNQHGFGTTGTGVWYPPNLSQMYSTYKTPVPETNIPGSTPTMPYFSGPVADDLIKYTIFNSSGIQIGNHNYMDVGLNSQPPNNTCKEESTSRHQAIFDNTTSLTDEHLNPIRENLGRQWKNCARKLGFTESQIDEIDHDYERDGLKEKVYQMLQKWLMREGTKGATVGKLAQALHQCCRIDLLNHLIRASQS
InterPro domains: - IPR011009: Protein kinase-like domain superfamily (homologous_superfamily) [6-299]
- IPR037934: RIP1, Death domain (domain) [568-653]
- IPR011029: Death-like domain superfamily (homologous_superfamily) [553-656]
- IPR008271: Serine/threonine-protein kinase, active site (active_site) [134-146]
- IPR001245: Serine-threonine/tyrosine-protein kinase, catalytic domain (domain) [21-285]
- IPR025735: RIP homotypic interaction motif (binding_site) [521-536]
- IPR000719: Protein kinase domain (domain) [17-290]
- IPR000488: Death domain (domain) [558-654]
- IPR051681: Serine/Threonine Kinases and Pseudokinases (family) [16-286]
Interaction partners: - TNF receptor-associated factor 2
- FAS-associated death domain protein
- Baculoviral IAP repeat-containing protein 2
- NF-kappa-B essential modulator
- Tumor necrosis factor receptor superfamily member 1A
- TGF-beta-activated kinase 1 and MAP3K7-binding protein 2
- Receptor-interacting serine/threonine-protein kinase 3
- Tumor necrosis factor receptor type 1-associated DEATH domain protein
- Caspase-8
- TNF receptor-associated factor 6
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0016740 (transferase activity), GO:0140096 (catalytic activity, acting on a protein), GO:0005515 (protein binding), GO:0004672 (protein kinase activity), GO:0005102 (signaling receptor binding), GO:0016772 (transferase activity, transferring phosphorus-containing groups), GO:0016773 (phosphotransferase activity, alcohol group as acceptor), GO:0005126 (cytokine receptor binding), GO:0004674 (protein serine/threonine kinase activity), GO:0016301 (kinase activity)
Biological Process (BP): GO:0008150 (biological process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0023052 (signaling), GO:0032501 (multicellular organismal process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0032502 (developmental process), GO:0009987 (cellular process), GO:0008152 (metabolic process), GO:0044419 (biological process involved in interspecies interaction between organisms), GO:0042592 (homeostatic process), GO:0002376 (immune system process), GO:0009605 (response to external stimulus), GO:0048856 (anatomical structure development), GO:0042221 (response to chemical), GO:0045321 (leukocyte activation), GO:0051239 (regulation of multicellular organismal process), GO:0048871 (multicellular organismal-level homeostasis), GO:0050793 (regulation of developmental process), GO:0009607 (response to biotic stimulus), GO:0008219 (cell death), GO:0050794 (regulation of cellular process), GO:0048583 (regulation of response to stimulus), GO:0051716 (cellular response to stimulus), GO:0023051 (regulation of signaling), GO:0001776 (leukocyte homeostasis), GO:0051707 (response to other organism), GO:0007165 (signal transduction), GO:0040012 (regulation of locomotion), GO:0048869 (cellular developmental process), GO:0023056 (positive regulation of signaling), GO:0007275 (multicellular organism development), GO:0001775 (cell activation), GO:0048584 (positive regulation of response to stimulus), GO:0019222 (regulation of metabolic process), GO:0032879 (regulation of localization), GO:0002682 (regulation of immune system process), GO:0044237 (cellular metabolic process), GO:0002520 (immune system development), GO:0009893 (positive regulation of metabolic process), GO:0065009 (regulation of molecular function), GO:0006950 (response to stress), GO:0051094 (positive regulation of developmental process), GO:0007154 (cell communication), GO:0048522 (positive regulation of cellular process), GO:0002260 (lymphocyte homeostasis), GO:0010942 (positive regulation of cell death), GO:0012501 (programmed cell death), GO:0043207 (response to external biotic stimulus), GO:2000145 (regulation of cell motility), GO:0002685 (regulation of leukocyte migration), GO:0048468 (cell development), GO:0030154 (cell differentiation), GO:0048731 (system development), GO:0048513 (animal organ development), GO:0009966 (regulation of signal transduction), GO:0060255 (regulation of macromolecule metabolic process), GO:1903706 (regulation of hemopoiesis), GO:0046649 (lymphocyte activation), GO:0031341 (regulation of cell killing), GO:0010035 (response to inorganic substance), GO:0002697 (regulation of immune effector process), GO:0009615 (response to virus), GO:1902074 (response to salt), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0045595 (regulation of cell differentiation), GO:0007166 (cell surface receptor signaling pathway), GO:0051128 (regulation of cellular component organization), GO:0009615 (response to virus), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:0009967 (positive regulation of signal transduction), GO:0045597 (positive regulation of cell differentiation), GO:0050790 (regulation of catalytic activity), GO:0044093 (positive regulation of molecular function), GO:0051049 (regulation of transport), GO:0035556 (intracellular signal transduction), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0002269 (leukocyte activation involved in inflammatory response), GO:0060341 (regulation of cellular localization), GO:0006952 (defense response), GO:1901700 (response to oxygen-containing compound), GO:0010033 (response to organic substance), GO:0070265 (necrotic cell death), GO:0098542 (defense response to other organism), GO:0048872 (homeostasis of number of cells), GO:2000026 (regulation of multicellular organismal development), GO:0050776 (regulation of immune response), GO:0042127 (regulation of cell population proliferation), GO:0010941 (regulation of cell death), GO:0031325 (positive regulation of cellular metabolic process), GO:0010646 (regulation of cell communication), GO:0070887 (cellular response to chemical stimulus), GO:0033554 (cellular response to stress), GO:0031323 (regulation of cellular metabolic process), GO:0010647 (positive regulation of cell communication), GO:0080090 (regulation of primary metabolic process), GO:0048534 (hematopoietic or lymphoid organ development), GO:0034599 (cellular response to oxidative stress), GO:0048535 (lymph node development), GO:0048535 (lymph node development), GO:0051100 (negative regulation of binding), GO:0051246 (regulation of protein metabolic process), GO:0043067 (regulation of programmed cell death), GO:0002703 (regulation of leukocyte mediated immunity), GO:0010940 (positive regulation of necrotic cell death), GO:0048732 (gland development), GO:0030334 (regulation of cell migration), GO:0048536 (spleen development), GO:0070663 (regulation of leukocyte proliferation), GO:0048538 (thymus development), GO:0010468 (regulation of gene expression), GO:0030098 (lymphocyte differentiation), GO:0051223 (regulation of protein transport), GO:0090276 (regulation of peptide hormone secretion), GO:0071677 (positive regulation of mononuclear cell migration), GO:0030335 (positive regulation of cell migration), GO:1902533 (positive regulation of intracellular signal transduction), GO:0071675 (regulation of mononuclear cell migration), GO:2000379 (positive regulation of reactive oxygen species metabolic process), GO:0043085 (positive regulation of catalytic activity), GO:1901701 (cellular response to oxygen-containing compound), GO:0097300 (programmed necrotic cell death), GO:0002819 (regulation of adaptive immune response), GO:0051249 (regulation of lymphocyte activation), GO:0030097 (hemopoiesis), GO:0034097 (response to cytokine), GO:0002521 (leukocyte differentiation), GO:0010562 (positive regulation of phosphorus metabolic process), GO:0071310 (cellular response to organic substance), GO:0043068 (positive regulation of programmed cell death), GO:0062197 (cellular response to chemical stress), GO:0060284 (regulation of cell development), GO:2001235 (positive regulation of apoptotic signaling pathway), GO:0010628 (positive regulation of gene expression), GO:2001233 (regulation of apoptotic signaling pathway), GO:0010939 (regulation of necrotic cell death), GO:0140546 (defense response to symbiont), GO:0071241 (cellular response to inorganic substance), GO:0033993 (response to lipid), GO:0006915 (apoptotic process), GO:0043029 (T cell homeostasis), GO:0051247 (positive regulation of protein metabolic process), GO:0042110 (T cell activation), GO:0042542 (response to hydrogen peroxide), GO:0051338 (regulation of transferase activity), GO:0043269 (regulation of monoatomic ion transport), GO:0031329 (regulation of cellular catabolic process), GO:1902531 (regulation of intracellular signal transduction), GO:0051174 (regulation of phosphorus metabolic process), GO:0097300 (programmed necrotic cell death), GO:0042981 (regulation of apoptotic process), GO:0050670 (regulation of lymphocyte proliferation), GO:0045619 (regulation of lymphocyte differentiation), GO:0002822 (regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains), GO:0050863 (regulation of T cell activation), GO:0032944 (regulation of mononuclear cell proliferation), GO:1903131 (mononuclear cell differentiation), GO:0016310 (phosphorylation), GO:0043549 (regulation of kinase activity), GO:1903131 (mononuclear cell differentiation), GO:0043410 (positive regulation of MAPK cascade), GO:0002573 (myeloid leukocyte differentiation), GO:0034614 (cellular response to reactive oxygen species), GO:0031401 (positive regulation of protein modification process), GO:0032872 (regulation of stress-activated MAPK cascade), GO:0043408 (regulation of MAPK cascade), GO:0043065 (positive regulation of apoptotic process), GO:0051347 (positive regulation of transferase activity), GO:0002824 (positive regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains), GO:0031399 (regulation of protein modification process), GO:0070266 (necroptotic process), GO:2000401 (regulation of lymphocyte migration), GO:2001238 (positive regulation of extrinsic apoptotic signaling pathway), GO:0006468 (protein phosphorylation), GO:0019220 (regulation of phosphate metabolic process), GO:0071396 (cellular response to lipid), GO:0071248 (cellular response to metal ion), GO:0002706 (regulation of lymphocyte mediated immunity), GO:0043122 (regulation of I-kappaB kinase/NF-kappaB signaling), GO:0062098 (regulation of programmed necrotic cell death), GO:0034612 (response to tumor necrosis factor), GO:2001236 (regulation of extrinsic apoptotic signaling pathway), GO:0043123 (positive regulation of I-kappaB kinase/NF-kappaB signaling), GO:0070301 (cellular response to hydrogen peroxide), GO:0001932 (regulation of protein phosphorylation), GO:0060544 (regulation of necroptotic process), GO:0045859 (regulation of protein kinase activity), GO:0035303 (regulation of dephosphorylation), GO:0070227 (lymphocyte apoptotic process), GO:0042327 (positive regulation of phosphorylation), GO:0043406 (positive regulation of MAP kinase activity), GO:0001934 (positive regulation of protein phosphorylation), GO:0042325 (regulation of phosphorylation), GO:0060544 (regulation of necroptotic process), GO:0033674 (positive regulation of kinase activity), GO:0097028 (dendritic cell differentiation), GO:0042129 (regulation of T cell proliferation), GO:0071356 (cellular response to tumor necrosis factor), GO:0071900 (regulation of protein serine/threonine kinase activity)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0016020 (membrane), GO:0005829 (cytosol), GO:0005737 (cytoplasm), GO:0071944 (cell periphery), GO:0005739 (mitochondrion), GO:0043229 (intracellular organelle), GO:0043227 (membrane-bounded organelle), GO:0005886 (plasma membrane), GO:0043231 (intracellular membrane-bounded organelle), GO:0005634 (nucleus)