RIPK2 (RIP2/RICK/CARDIAK) is a cytoplasmic signaling protein with an N-terminal kinase domain, a C-terminal caspase-recruitment domain (CARD), and an intermediate linker. It is the essential adaptor of the intracellular bacterial sensors NOD1 and NOD2: upon detection of peptidoglycan fragments (iE-DAP for NOD1, muramyl dipeptide for NOD2) the activated receptors oligomerize and recruit RIPK2 through homotypic CARD-CARD contacts, nucleating helical RIPK2 CARD filaments (RIPosomes). Recruited RIPK2 is then conjugated with K63-linked polyubiquitin (by XIAP and cIAP1/2) and M1/linear chains (by LUBAC, recruited via XIAP), and these chains on RIPK2 serve as docking platforms that recruit the TAK1-TAB and IKK/NEMO complexes, driving canonical NF-kappaB activation and MAPK (p38/JNK) signaling and the resulting proinflammatory cytokine program. RIPK2 is a bona fide dual-specificity autokinase (serine/threonine autophosphorylation at Ser176 and tyrosine autophosphorylation at Tyr474, with activation coupled to kinase-domain dimerization), but its catalytic activity is dispensable for NOD1/NOD2-driven NF-kappaB output; the kinase domain instead contributes a structural surface for XIAP binding. RIPK2 also transduces signals from TLR2/3/4 and the IL-1/IL-18 receptors and contributes to T-cell receptor signaling (BCL10 phosphorylation) in adaptive immunity. It localizes to the cytosol and is recruited to the plasma membrane with NOD2, with a minor endoplasmic-reticulum pool. RIPK2 and NOD2 are central to intestinal immune homeostasis, and NOD2/XIAP pathway defects cause Crohn disease and X-linked lymphoproliferative syndrome type 2.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000165 MAPK cascade | IEA GO_REF:0000108 | REMOVE | Summary: MAPK cascade (inter-ontology IEA). Reason: Inter-ontology IEA derived from the GO:0004706 JUN kinase kinase kinase activity annotation, which is itself a mis-propagated IBA (RIPK2 is not a MAP3K/JNKKK). RIPK2 acts upstream of the MAPK cascade only indirectly, via ubiquitin-scaffold recruitment of TAK1; it is not a component enzyme of the MAPK cascade. |
| GO:0001819 positive regulation of cytokine production | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Positive regulation of cytokine production (general). Reason: Accurate but general downstream outcome of NOD/TLR signaling; captured more specifically by the NOD1/NOD2 signaling and NF-kB annotations. Not a distinct molecular role. |
| GO:0002250 adaptive immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Adaptive immune response (TCR/T cell role). Reason: RIPK2 contributes to TCR signaling and T-cell responses (PMID:11894098), but adaptive immunity is a secondary, pleiotropic role relative to the core NOD1/NOD2 innate function. |
| GO:0002250 adaptive immune response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Adaptive immune response (ISS). Reason: Same as the orthology-based annotation; real but non-core. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Protein kinase activity (general parent). Reason: RIPK2 is a bona fide autokinase, so this is not removed; but the general parent is less informative than the serine/threonine (GO:0004674) and tyrosine (GO:0004713) activities, and kinase catalysis is not the core signaling function (it is dispensable for NOD1/NOD2->NF-kB output; PMID:30026309, PMID:29452636). |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Protein serine/threonine kinase activity. Reason: Bona fide: RIPK2 autophosphorylates on Ser176 (PMID:16824733). Retained as a real activity but marked non-core because catalysis is dispensable for NOD1/NOD2 signaling output. |
| GO:0004674 protein serine/threonine kinase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Protein serine/threonine kinase activity (ISS). Reason: Real kinase activity; non-core per the kinase-dispensability evidence. |
| GO:0004674 protein serine/threonine kinase activity | TAS PMID:9642260 RIP2 is a novel NF-kappaB-activating and cell death-inducing... | KEEP AS NON CORE | Summary: Protein serine/threonine kinase activity (TAS). Reason: Real kinase activity; non-core. |
| GO:0004674 protein serine/threonine kinase activity | TAS Reactome:R-HSA-202459 | KEEP AS NON CORE | Summary: Protein serine/threonine kinase activity (Reactome TAS). Reason: Real kinase activity; non-core. |
| GO:0004706 JUN kinase kinase kinase activity | IBA GO_REF:0000033 | REMOVE | Summary: JUN kinase kinase kinase activity (IBA). Reason: Mis-propagated IBA. RIPK2 belongs to the RIP kinase family and is a CARD-adaptor autokinase; it is not a MAP3K that phosphorylates MKK4/MKK7 to activate JNK. JNK/p38 activation downstream of NOD2 is executed by TAK1 (MAP3K7), recruited to ubiquitinated RIPK2. This is an over-propagated electronic/phylogenetic inference argued against on biological grounds. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN001147669 Ancestral node propagating JUN kinase kinase kinase (MAP3K) activity; RIPK2 is a RIP-family CARD adaptor autokinase, not a JNKKK. JNK/p38 activation downstream of NOD2 is executed by TAK1, not RIPK2. |
| GO:0004713 protein tyrosine kinase activity | EXP PMID:21123652 Inhibition of RIP2's tyrosine kinase activity limits NOD2-dr... | KEEP AS NON CORE | Summary: Protein tyrosine kinase activity (EXP). Reason: Bona fide: RIPK2 autophosphorylates on Tyr474 (PMID:21123652); it is a dual-specificity autokinase. Retained as a real experimental activity but marked non-core: kinase-dead reconstitution (K47R and D146N) fully restores NOD2 signaling (PMID:30026309), so catalysis is not the essential output. Supporting Evidence: PMID:21123652 autophosphorylation on Tyr 474 (Y474). This phosphorylation event is necessary |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Protein tyrosine kinase activity (IEA/Rhea). Reason: Real tyrosine autokinase activity; non-core. |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IEA GO_REF:0000003 | KEEP AS NON CORE | Summary: Non-membrane spanning protein tyrosine kinase activity (IEA/EC). Reason: Consistent with the experimentally supported tyrosine autophosphorylation; RIPK2 is a cytoplasmic (non-membrane-spanning) kinase. Marked non-core as catalysis is dispensable for signaling output. |
| GO:0005102 signaling receptor binding | IPI PMID:24790089 The molecular chaperone HSP70 binds to and stabilizes NOD2, ... | MODIFY | Summary: Binds the pattern-recognition receptor NOD2. Reason: RIPK2 engages NOD2 through a homotypic CARD-CARD interaction; CARD domain binding is the informative molecular function, more specific than the generic signaling receptor binding. Proposed replacements: CARD domain binding |
| GO:0005515 protein binding | IPI PMID:11432859 Cop, a caspase recruitment domain-containing protein and inh... | REMOVE | Summary: Generic protein binding (interaction reported in a caspase-1/COP study). Reason: Interaction reported in a caspase-1/COP study; generic and uninformative. |
| GO:0005515 protein binding | IPI PMID:11536016 Regulation of IL-1beta generation by Pseudo-ICE and ICEBERG,... | REMOVE | Summary: Generic protein binding (interaction reported in a Pseudo-ICE/ICEBERG study). Reason: Interaction reported in a Pseudo-ICE/ICEBERG study; generic and uninformative. |
| GO:0005515 protein binding | IPI PMID:15383541 INCA, a novel human caspase recruitment domain protein that ... | REMOVE | Summary: Generic protein binding (interaction reported in an INCA/caspase-1 study). Reason: Interaction reported in an INCA/caspase-1 study; generic and uninformative. |
| GO:0005515 protein binding | IPI PMID:16418290 Caspase recruitment domain protein 6 is a microtubule-intera... | REMOVE | Summary: Generic protein binding (interaction with CARD6/microtubule-associated CARD protein). Reason: Interaction with CARD6/microtubule-associated CARD protein; generic protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:17054981 Solution structure of NOD1 CARD and mutational analysis of i... | REMOVE | Summary: Generic protein binding (interaction with NOD1). Reason: Interaction with NOD1; the functional CARD-CARD recruitment is captured by GO:0050700 CARD domain binding. |
| GO:0005515 protein binding | IPI PMID:19337385 Evaluation of Nod-like receptor (NLR) effector domain intera... | REMOVE | Summary: Generic protein binding (RIPK2 self-interaction). Reason: RIPK2 self-interaction; captured by GO:0042802 identical protein binding and GO:0042803 homodimerization (filament assembly). |
| GO:0005515 protein binding | IPI PMID:19337385 Evaluation of Nod-like receptor (NLR) effector domain intera... | REMOVE | Summary: Generic protein binding (interaction with NOD2). Reason: Interaction with NOD2; captured by GO:0050700 CARD domain binding. |
| GO:0005515 protein binding | IPI PMID:19337385 Evaluation of Nod-like receptor (NLR) effector domain intera... | REMOVE | Summary: Generic protein binding (interaction with NOD1). Reason: Interaction with NOD1; captured by GO:0050700 CARD domain binding. |
| GO:0005515 protein binding | IPI PMID:19667203 XIAP mediates NOD signaling via interaction with RIP2. | MODIFY | Summary: Binds the E3 ubiquitin ligase that ubiquitinates RIPK2 (XIAP or cIAP1/2). Reason: RIPK2 is the ubiquitination substrate/scaffold; its binding to the RING E3 ligases XIAP (BIR2) and cIAP1/2 is central to NOD signaling. Ubiquitin protein ligase binding is the informative molecular function, replacing generic protein binding. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:19667203 XIAP interacts with RIP2 via its BIR2 domain |
| GO:0005515 protein binding | IPI PMID:21887730 Control of NOD2 and Rip2-dependent innate immune activation ... | REMOVE | Summary: Generic protein binding (interaction with ARHGEF2/GEF-H1 (regulatory)). Reason: Interaction with ARHGEF2/GEF-H1 (regulatory); captured functionally in the NOD2/RIPK2 signaling process annotations. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: Generic protein binding (interaction with TRAF2 from a large interferon-interactome screen). Reason: Interaction with TRAF2 from a large interferon-interactome screen; generic. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: Generic protein binding (interaction with MAVS from an interferon-interactome screen). Reason: Interaction with MAVS from an interferon-interactome screen; generic and not an established RIPK2 function. |
| GO:0005515 protein binding | IPI PMID:21931591 cIAP1/2 are direct E3 ligases conjugating diverse types of u... | MODIFY | Summary: Binds the E3 ubiquitin ligase that ubiquitinates RIPK2 (XIAP or cIAP1/2). Reason: RIPK2 is the ubiquitination substrate/scaffold; its binding to the RING E3 ligases XIAP (BIR2) and cIAP1/2 is central to NOD signaling. Ubiquitin protein ligase binding is the informative molecular function, replacing generic protein binding. Proposed replacements: ubiquitin protein ligase binding |
| GO:0005515 protein binding | IPI PMID:21931591 cIAP1/2 are direct E3 ligases conjugating diverse types of u... | MODIFY | Summary: Binds the E3 ubiquitin ligase that ubiquitinates RIPK2 (XIAP or cIAP1/2). Reason: RIPK2 is the ubiquitination substrate/scaffold; its binding to the RING E3 ligases XIAP (BIR2) and cIAP1/2 is central to NOD signaling. Ubiquitin protein ligase binding is the informative molecular function, replacing generic protein binding. Proposed replacements: ubiquitin protein ligase binding |
| GO:0005515 protein binding | IPI PMID:21931591 cIAP1/2 are direct E3 ligases conjugating diverse types of u... | MODIFY | Summary: Binds the E3 ubiquitin ligase that ubiquitinates RIPK2 (XIAP or cIAP1/2). Reason: RIPK2 is the ubiquitination substrate/scaffold; its binding to the RING E3 ligases XIAP (BIR2) and cIAP1/2 is central to NOD signaling. Ubiquitin protein ligase binding is the informative molecular function, replacing generic protein binding. Proposed replacements: ubiquitin protein ligase binding |
| GO:0005515 protein binding | IPI PMID:21931826 Cigarette smoke extract (CSE) delays NOD2 expression and aff... | REMOVE | Summary: Generic protein binding (interaction with NOD2 (cigarette-smoke study)). Reason: Interaction with NOD2 (cigarette-smoke study); captured by CARD domain binding. |
| GO:0005515 protein binding | IPI PMID:22829933 TRIM27 negatively regulates NOD2 by ubiquitination and prote... | REMOVE | Summary: Generic protein binding (interaction with NOD2 (TRIM27 study)). Reason: Interaction with NOD2 (TRIM27 study); captured by CARD domain binding. |
| GO:0005515 protein binding | IPI PMID:23333941 Identification and characterization of receptor-interacting ... | REMOVE | Summary: Generic protein binding (interaction with TRAF3 (negative regulator)). Reason: Interaction with TRAF3 (negative regulator); generic protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:23818254 Disease-causing mutations in the XIAP BIR2 domain impair NOD... | MODIFY | Summary: Binds the E3 ubiquitin ligase that ubiquitinates RIPK2 (XIAP or cIAP1/2). Reason: RIPK2 is the ubiquitination substrate/scaffold; its binding to the RING E3 ligases XIAP (BIR2) and cIAP1/2 is central to NOD signaling. Ubiquitin protein ligase binding is the informative molecular function, replacing generic protein binding. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:23818254 XLP2-BIR2 mutations abolish the XIAP-RIPK2 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: Binds the E3 ubiquitin ligase that ubiquitinates RIPK2 (XIAP or cIAP1/2). Reason: RIPK2 is the ubiquitination substrate/scaffold; its binding to the RING E3 ligases XIAP (BIR2) and cIAP1/2 is central to NOD signaling. Ubiquitin protein ligase binding is the informative molecular function, replacing generic protein binding. Proposed replacements: ubiquitin protein ligase binding |
| GO:0005515 protein binding | IPI PMID:27812135 Characterization and Genetic Analyses of New Genes Coding fo... | REMOVE | Summary: Generic protein binding (interaction with NOD2 (NOD2-interactome study)). Reason: Interaction with NOD2 (NOD2-interactome study); captured by CARD domain binding. |
| GO:0005515 protein binding | IPI PMID:28436939 An inflammatory bowel disease-risk variant in INAVA decrease... | REMOVE | Summary: Generic protein binding (interaction with INAVA (PRR signaling amplifier)). Reason: Interaction with INAVA (PRR signaling amplifier); generic protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:29997244 LuTHy: a double-readout bioluminescence-based two-hybrid tec... | REMOVE | Summary: Generic protein binding (interaction with NOD1 from a two-hybrid technology paper). Reason: Interaction with NOD1 from a two-hybrid technology paper; captured by CARD domain binding. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MODIFY | Summary: Binds the E3 ubiquitin ligase that ubiquitinates RIPK2 (XIAP or cIAP1/2). Reason: RIPK2 is the ubiquitination substrate/scaffold; its binding to the RING E3 ligases XIAP (BIR2) and cIAP1/2 is central to NOD signaling. Ubiquitin protein ligase binding is the informative molecular function, replacing generic protein binding. Proposed replacements: ubiquitin protein ligase binding |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: Binds the E3 ubiquitin ligase that ubiquitinates RIPK2 (XIAP or cIAP1/2). Reason: RIPK2 is the ubiquitination substrate/scaffold; its binding to the RING E3 ligases XIAP (BIR2) and cIAP1/2 is central to NOD signaling. Ubiquitin protein ligase binding is the informative molecular function, replacing generic protein binding. Proposed replacements: ubiquitin protein ligase binding |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | REMOVE | Summary: Generic protein binding (interaction with TRAF2 from a kinase-interactome screen). Reason: Interaction with TRAF2 from a kinase-interactome screen; generic. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | REMOVE | Summary: Generic protein binding (interaction with TRAF3 from a kinase-interactome screen). Reason: Interaction with TRAF3 from a kinase-interactome screen; generic. |
| GO:0005515 protein binding | IPI PMID:35273242 Valosin-containing protein-regulated endoplasmic reticulum s... | REMOVE | Summary: Generic protein binding (interaction with NOD2 (VCP/ER-stress study)). Reason: Interaction with NOD2 (VCP/ER-stress study); captured by CARD domain binding. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | REMOVE | Summary: Generic protein binding (interaction with 14-3-3 (YWHAE) from a chaperone-interactome map). Reason: Interaction with 14-3-3 (YWHAE) from a chaperone-interactome map; regulatory, generic. |
| GO:0005515 protein binding | IPI PMID:37398436 AI-guided pipeline for protein-protein interaction drug disc... | REMOVE | Summary: Generic protein binding (interaction with NOD1 from an AI-PPI drug-discovery screen). Reason: Interaction with NOD1 from an AI-PPI drug-discovery screen; captured by CARD domain binding. |
| GO:0005515 protein binding | IPI PMID:38012669 OTUD1 ameliorates cerebral ischemic injury through inhibitin... | REMOVE | Summary: Generic protein binding (interaction with the deubiquitinase OTUD1 (removes K63 chains from RIPK2)). Reason: Interaction with the deubiquitinase OTUD1 (removes K63 chains from RIPK2); generic protein binding is uninformative and the functional relationship is deubiquitination, not a RIPK2 MF. |
| GO:0005515 protein binding | IPI PMID:38191507 Understanding the molecular mechanism of pathogenic variants... | MODIFY | Summary: Binds the E3 ubiquitin ligase that ubiquitinates RIPK2 (XIAP or cIAP1/2). Reason: RIPK2 is the ubiquitination substrate/scaffold; its binding to the RING E3 ligases XIAP (BIR2) and cIAP1/2 is central to NOD signaling. Ubiquitin protein ligase binding is the informative molecular function, replacing generic protein binding. Proposed replacements: ubiquitin protein ligase binding |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: ATP binding. Reason: Consistent with the kinase domain; real but non-core as catalysis is dispensable for signaling output. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoplasmic localization. Reason: Consistent, well-supported cytoplasmic localization of RIPK2. |
| GO:0005737 cytoplasm | IDA PMID:21887730 Control of NOD2 and Rip2-dependent innate immune activation ... | ACCEPT | Summary: Cytoplasmic localization. Reason: Consistent, well-supported cytoplasmic localization of RIPK2. Supporting Evidence: PMID:21887730 cytoplasmic and cytoskeletal association |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Cytoplasmic localization. Reason: Consistent, well-supported cytoplasmic localization of RIPK2. |
| GO:0005783 endoplasmic reticulum | EXP PMID:28656966 E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalli... | KEEP AS NON CORE | Summary: A fraction of endogenous RIPK2 co-fractionates with the ER, where it meets the ER-anchored E3 ligase ZNRF4 that limits NOD2 signalling. Reason: A fraction of RIPK2 localizes to the ER where it interacts with the E3 ligase ZNRF4 (PMID:28656966). ORGANELLES check (2026-11-05), which changes the action from ACCEPT: the full text shows endogenous RIPK2 in HCT116 cells in an ER fraction whose purity was checked with PDI against pan-cadherin for the plasma membrane, confirmed by confocal imaging of ectopic HA-RIPK2 with mCherry-Sec61beta. The ER pool is real, but RIPK2 is a soluble kinase with no signal peptide, TM segment or retention motif, so it is a recruited pool on the cytosolic face that stays at the root (BRSK2, A1CF precedent). It is non-core: the NOD2-RIPK2 signalling activity is placed in the cytosol and at the plasma membrane in core_functions, and the ER is where ZNRF4 down-regulates RIPK2, not where its kinase or scaffold function is shown. Supporting Evidence: PMID:28656966 Further separation of the membrane fraction into ER and PM revealed a previously undefined localization pattern for RIP2: a fraction of RIP2 was also localized to the ER PMID:28656966 The purity of fractions was assessed by detecting organelle-specific markers for ER (PDI) and PM (pan-cadherin). PMID:28656966 Collectively, these data demonstrate that a notable fraction of RIP2 localizes to the ER, suggesting the ER as the most likely site for the ZNRF4βRIP2 interactions that are critical for proper NOD2 regulation. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Endoplasmic reticulum localization (IEA from the UniProt subcellular-location keyword). Reason: Consistent with the experimental ER pool. ORGANELLES check (2026-11-05), which changes the action from ACCEPT to match the EXP row: SL-0095 maps UniProt's "Endoplasmic reticulum" line, tagged ECO:0000269 to PMID:28656966 only, so this row adds no independent line. The claim holds (endogenous RIPK2 in a PDI-marked ER fraction) but describes a recruited, non-core pool of a soluble kinase; it stays at the root. Supporting Evidence: file:human/RIPK2/RIPK2-uniprot.txt Endoplasmic reticulum {ECO:0000269|PubMed:28656966}. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Cytosolic localization. Reason: RIPK2 is a cytosolic signaling adaptor. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-168184 | ACCEPT | Summary: Cytosolic localization (Reactome TAS). Reason: RIPK2 is a cytosolic signaling adaptor. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-168405 | ACCEPT | Summary: Cytosolic localization (Reactome TAS). Reason: RIPK2 is a cytosolic signaling adaptor. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-193656 | ACCEPT | Summary: Cytosolic localization (Reactome TAS). Reason: RIPK2 is a cytosolic signaling adaptor. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202459 | ACCEPT | Summary: Cytosolic localization (Reactome TAS). Reason: RIPK2 is a cytosolic signaling adaptor. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-450337 | ACCEPT | Summary: Cytosolic localization (Reactome TAS). Reason: RIPK2 is a cytosolic signaling adaptor. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-450346 | ACCEPT | Summary: Cytosolic localization (Reactome TAS). Reason: RIPK2 is a cytosolic signaling adaptor. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-622415 | ACCEPT | Summary: Cytosolic localization (Reactome TAS). Reason: RIPK2 is a cytosolic signaling adaptor. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-688136 | ACCEPT | Summary: Cytosolic localization (Reactome TAS). Reason: RIPK2 is a cytosolic signaling adaptor. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-688137 | ACCEPT | Summary: Cytosolic localization (Reactome TAS). Reason: RIPK2 is a cytosolic signaling adaptor. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-688985 | ACCEPT | Summary: Cytosolic localization (Reactome TAS). Reason: RIPK2 is a cytosolic signaling adaptor. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-706479 | ACCEPT | Summary: Cytosolic localization (Reactome TAS). Reason: RIPK2 is a cytosolic signaling adaptor. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-741386 | ACCEPT | Summary: Cytosolic localization (Reactome TAS). Reason: RIPK2 is a cytosolic signaling adaptor. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-741411 | ACCEPT | Summary: Cytosolic localization (Reactome TAS). Reason: RIPK2 is a cytosolic signaling adaptor. |
| GO:0005856 cytoskeleton | IDA PMID:21887730 Control of NOD2 and Rip2-dependent innate immune activation ... | KEEP AS NON CORE | Summary: Cytoskeleton association. Reason: Reported via colocalization with microtubule-associated GEF-H1 (PMID:21887730); peripheral/regulatory, non-core. |
| GO:0005886 plasma membrane | IDA PMID:17355968 The NOD2-RICK complex signals from the plasma membrane. | ACCEPT | Summary: Active at the plasma membrane with NOD2. Reason: NOD2 recruits RICK to the plasma membrane, from where the complex signals (PMID:17355968). Supporting Evidence: PMID:17355968 NOD2 promotes the membrane recruitment of |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane localization (IEA). Reason: Consistent with NOD2-dependent membrane recruitment. |
| GO:0006915 apoptotic process | IDA PMID:16920334 Protective role of Cop in Rip2/caspase-1/caspase-4-mediated ... | MARK AS OVER ANNOTATED | Summary: Apoptotic process (overexpression). Reason: RIPK2 overexpression can induce caspase-1/caspase-4-dependent cell death via its CARD (PMID:16920334), but the physiological core role of RIPK2 is NF-kB/MAPK activation, not apoptosis induction. Likely over-annotation from overexpression artefact. |
| GO:0006915 apoptotic process | TAS PMID:9642260 RIP2 is a novel NF-kappaB-activating and cell death-inducing... | MARK AS OVER ANNOTATED | Summary: Apoptotic process (TAS, overexpression). Reason: Based on early overexpression showing RIP2 as a "cell death-inducing kinase" (PMID:9642260); physiological role is inflammatory signaling, not apoptosis. |
| GO:0006954 inflammatory response | TAS PMID:9705938 Identification of CARDIAK, a RIP-like kinase that associates... | KEEP AS NON CORE | Summary: Inflammatory response (broad). Reason: Accurate but broad; captured more specifically by NOD/NF-kB annotations. |
| GO:0007165 signal transduction | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Signal transduction (general parent, IBA). Reason: Correct but uninformative high-level term; the specific NOD1/NOD2 and NF-kB annotations are preferred. |
| GO:0007165 signal transduction | TAS PMID:9642260 RIP2 is a novel NF-kappaB-activating and cell death-inducing... | KEEP AS NON CORE | Summary: Signal transduction (general, TAS). Reason: Correct but uninformative; specific process terms preferred. |
| GO:0007249 canonical NF-kappaB signal transduction | IEA GO_REF:0000107 | ACCEPT | Summary: Canonical NF-kappaB signaling. Reason: RIPK2 is an essential positive component of canonical NF-kB signaling downstream of NOD1/NOD2. |
| GO:0007249 canonical NF-kappaB signal transduction | ISS GO_REF:0000024 | ACCEPT | Summary: Canonical NF-kappaB signaling (ISS). Reason: Core role; well supported across orthologs. |
| GO:0030274 LIM domain binding | IPI PMID:15657077 TRIP6 is a RIP2-associated common signaling component of mul... | KEEP AS NON CORE | Summary: LIM domain binding (TRIP6). Reason: Experimental interaction with the LIM protein TRIP6, a shared NF-kB signaling component (PMID:15657077). Real but peripheral; non-core. |
| GO:0031398 positive regulation of protein ubiquitination | IMP PMID:15620648 The Crohn's disease protein, NOD2, requires RIP2 in order to... | KEEP AS NON CORE | Summary: Required for NOD2-induced NEMO ubiquitination. Reason: RIPK2 scaffolds NOD2-induced NEMO ubiquitination (PMID:15620648); the specific, core aspect is captured by GO:1902523 positive regulation of protein K63-linked ubiquitination, so this general term is kept non-core. Supporting Evidence: PMID:15620648 NOD2-dependent ubiquitinylation of NEMO is dependent on the scaffolding protein |
| GO:0031398 positive regulation of protein ubiquitination | NAS PMID:22412986 Activation of interferon regulatory factor 5 by site specifi... | KEEP AS NON CORE | Summary: Positive regulation of protein ubiquitination (NAS). Reason: Consistent with the scaffold role; general NAS statement kept non-core. |
| GO:0031982 vesicle | IDA PMID:21887730 Control of NOD2 and Rip2-dependent innate immune activation ... | KEEP AS NON CORE | Summary: Vesicle localization. Reason: Reported in the GEF-H1 study (PMID:21887730); peripheral, non-core. |
| GO:0032727 positive regulation of interferon-alpha production | NAS PMID:22412986 Activation of interferon regulatory factor 5 by site specifi... | KEEP AS NON CORE | Summary: Positive regulation of IFN-alpha production (NAS). Reason: Indirect/pleiotropic downstream effect (via IRF5); non-core. |
| GO:0032728 positive regulation of interferon-beta production | NAS PMID:22412986 Activation of interferon regulatory factor 5 by site specifi... | KEEP AS NON CORE | Summary: Positive regulation of IFN-beta production (NAS). Reason: Indirect/pleiotropic downstream effect; non-core. |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:11432859 Cop, a caspase recruitment domain-containing protein and inh... | KEEP AS NON CORE | Summary: Positive regulation of IL-1beta production. Reason: RIPK2/CARDIAK can promote caspase-1 oligomerization and IL-1beta generation (PMID:11432859); downstream/secondary to the NF-kB adaptor role. |
| GO:0032735 positive regulation of interleukin-12 production | NAS PMID:22412986 Activation of interferon regulatory factor 5 by site specifi... | KEEP AS NON CORE | Summary: Positive regulation of IL-12 production (NAS). Reason: Downstream cytokine outcome; non-core. |
| GO:0032755 positive regulation of interleukin-6 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of IL-6 production (IEA). Reason: Downstream cytokine outcome; non-core. |
| GO:0032760 positive regulation of tumor necrosis factor production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of TNF production (IEA). Reason: Downstream cytokine outcome; non-core. |
| GO:0032991 protein-containing complex | IDA PMID:11536016 Regulation of IL-1beta generation by Pseudo-ICE and ICEBERG,... | KEEP AS NON CORE | Summary: Member of a protein-containing complex (generic). Reason: RIPK2 is part of the NOD signalosome/RIPosome, but protein-containing complex is an uninformative generic term; no more specific GO complex term currently fits. |
| GO:0032991 protein-containing complex | IDA PMID:15383541 INCA, a novel human caspase recruitment domain protein that ... | KEEP AS NON CORE | Summary: Member of a protein-containing complex (generic). Reason: RIPK2 is part of the NOD signalosome/RIPosome, but protein-containing complex is an uninformative generic term; no more specific GO complex term currently fits. |
| GO:0032991 protein-containing complex | IDA PMID:21887730 Control of NOD2 and Rip2-dependent innate immune activation ... | KEEP AS NON CORE | Summary: Member of a protein-containing complex (generic). Reason: RIPK2 is part of the NOD signalosome/RIPosome, but protein-containing complex is an uninformative generic term; no more specific GO complex term currently fits. |
| GO:0032991 protein-containing complex | IMP PMID:11432859 Cop, a caspase recruitment domain-containing protein and inh... | KEEP AS NON CORE | Summary: Member of a protein-containing complex (generic). Reason: RIPK2 is part of the NOD signalosome/RIPosome, but protein-containing complex is an uninformative generic term; no more specific GO complex term currently fits. |
| GO:0034134 toll-like receptor 2 signaling pathway | IDA PMID:11894098 RICK/Rip2/CARDIAK mediates signalling for receptors of the i... | KEEP AS NON CORE | Summary: Acts in TLR2 signaling. Reason: RIPK2 acts downstream of TLR2 (PMID:11894098); real but secondary to the core NOD role, and TLR-dependence has been debated. |
| GO:0035591 signaling adaptor activity | IDA PMID:16824733 Identification of a regulatory autophosphorylation site in t... | ACCEPT | Summary: Signaling adaptor activity for NOD1/NOD2 (CORE). Reason: RIPK2 functions as the signaling adaptor that couples activated NOD1/NOD2 to downstream NF-kB/MAPK machinery. This is the GO-CAM molecular function for RIPK2 in the NOD1/NOD2 models. |
| GO:0035591 signaling adaptor activity | IDA PMID:29452636 Disruption of XIAP-RIP2 Association Blocks NOD2-Mediated Inf... | ACCEPT | Summary: Signaling adaptor activity (CORE). Reason: Its essential role is as a ubiquitinated scaffold/adaptor; catalysis is dispensable (PMID:29452636). Supporting Evidence: PMID:29452636 RIP2 is dispensable for NOD2 signaling. Rather, the conformation of the RIP2 |
| GO:0035591 signaling adaptor activity | IDA PMID:30026309 Small molecule inhibitors reveal an indispensable scaffoldin... | ACCEPT | Summary: Signaling adaptor activity (CORE). Reason: Small-molecule inhibitor study established an indispensable scaffolding role of RIPK2 in NOD2 signaling (PMID:30026309). Supporting Evidence: PMID:30026309 showing that the catalytic function is not needed for RIPK2's role in NOD2 |
| GO:0035591 signaling adaptor activity | IDA PMID:30279485 RIP2 filament formation is required for NOD2 dependent NF-ΞΊB... | ACCEPT | Summary: Signaling adaptor activity (CORE). Reason: RIP2 filament formation (adaptor polymerization) is required for NOD2-dependent NF-kB signaling (PMID:30279485). Supporting Evidence: PMID:30279485 long filaments mediated by its caspase recruitment domain (CARD) |
| GO:0035591 signaling adaptor activity | IDA PMID:30478312 Structural basis of RIP2 activation and signaling. | ACCEPT | Summary: Signaling adaptor activity (CORE). Reason: Structural basis of RIP2 activation as the NOD1/NOD2 adaptor (PMID:30478312). Supporting Evidence: PMID:30478312 critical for signal propagation of the |
| GO:0042742 defense response to bacterium | IDA PMID:16824733 Identification of a regulatory autophosphorylation site in t... | ACCEPT | Summary: Defense response to bacterium. Reason: RIPK2 is required for antibacterial NOD1/NOD2 responses. |
| GO:0042742 defense response to bacterium | IDA PMID:29452636 Disruption of XIAP-RIP2 Association Blocks NOD2-Mediated Inf... | ACCEPT | Summary: Defense response to bacterium. Reason: Core innate antibacterial role downstream of NOD1/NOD2. |
| GO:0042742 defense response to bacterium | IEA GO_REF:0000117 | ACCEPT | Summary: Defense response to bacterium (IEA). Reason: Consistent with the core innate role. |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Self-association / homo-oligomerization. Reason: RIPK2 self-association detected in a high-throughput interactome screen; the functional homo-oligomerization (filament assembly) is captured by the ACCEPTed GO:0042803 homodimerization annotation. |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Self-association (interactome). Reason: RIPK2 self-association detected in a high-throughput interactome screen; the functional homo-oligomerization (filament assembly) is captured by the ACCEPTed GO:0042803 homodimerization annotation. |
| GO:0042803 protein homodimerization activity | IDA PMID:19337385 Evaluation of Nod-like receptor (NLR) effector domain intera... | ACCEPT | Summary: Homodimerization activity (filament assembly). Reason: RIPK2 CARD homodimerizes/oligomerizes (PMID:19337385), underpinning RIPosome filament formation. Supporting Evidence: PMID:19337385 homodimerization of the RIPK2 |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Regulation of apoptotic process (InterPro IEA). Reason: Domain-based electronic inference; RIPK2 physiological core role is inflammatory signaling, not apoptosis regulation. |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Positive regulation of apoptotic process (InterPro IEA). Reason: Domain-based electronic inference; over-annotation given the core NF-kB role. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: Positive regulation of canonical NF-kappaB (IBA, CORE). Reason: Phylogenetically well-grounded (PTN002892800) and supported by direct experimental evidence on RIPK2 itself. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IDA PMID:10329646 Nod1, an Apaf-1-like activator of caspase-9 and nuclear fact... | ACCEPT | Summary: Positive regulation of canonical NF-kappaB (IDA, CORE). Reason: RIPK2 (RICK) is a direct activator of NF-kB downstream of NOD1 (PMID:10329646). |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IEA GO_REF:0000120 | ACCEPT | Summary: Positive regulation of canonical NF-kappaB (IEA). Reason: Consistent core role. |
| GO:0045087 innate immune response | IBA GO_REF:0000033 | ACCEPT | Summary: Innate immune response (IBA, CORE). Reason: Well-grounded phylogenetic and experimental support. |
| GO:0045087 innate immune response | IDA PMID:23806334 OTULIN restricts Met1-linked ubiquitination to control innat... | ACCEPT | Summary: Innate immune response (IDA, CORE). Reason: RIPK2 is the predominant NOD2-regulated Met1-ubiquitination substrate controlling innate signaling (PMID:23806334). Supporting Evidence: PMID:23806334 RIPK2 as the predominant NOD2-regulated |
| GO:0045087 innate immune response | IEA GO_REF:0000120 | ACCEPT | Summary: Innate immune response (IEA). Reason: Consistent core role. |
| GO:0045087 innate immune response | ISS GO_REF:0000024 | ACCEPT | Summary: Innate immune response (ISS). Reason: Consistent core role. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | NAS PMID:22412986 Activation of interferon regulatory factor 5 by site specifi... | MARK AS OVER ANNOTATED | Summary: Positive regulation of transcription by RNA Pol II (NAS). Reason: Indirect: RIPK2 drives NF-kB/IRF5 activation which regulates transcription, but RIPK2 does not act directly at Pol II promoters. Over-annotation of a distal downstream effect. |
| GO:0050700 CARD domain binding | IDA PMID:10329646 Nod1, an Apaf-1-like activator of caspase-9 and nuclear fact... | ACCEPT | Summary: CARD domain binding (NOD1 recruitment, CORE). Reason: RIPK2 CARD binds the CARD of NOD1 (PMID:10329646); this CARD-CARD recruitment is the core adaptor function. |
| GO:0050700 CARD domain binding | IPI PMID:11087742 Nod2, a Nod1/Apaf-1 family member that is restricted to mono... | ACCEPT | Summary: CARD domain binding (NOD2 recruitment, CORE). Reason: RIPK2 CARD binds NOD2 CARD via a homophilic CARD-CARD interaction (PMID:11087742). Supporting Evidence: PMID:11087742 interacted with the serine-threonine kinase RICK via a homophilic CARD-CARD |
| GO:0050852 T cell receptor signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: T cell receptor signaling pathway (ISS). Reason: Adaptive role (BCL10 phosphorylation); secondary to core NOD function. |
| GO:0050852 T cell receptor signaling pathway | TAS Reactome:R-HSA-202403 | KEEP AS NON CORE | Summary: T cell receptor signaling pathway (TAS). Reason: Adaptive role; non-core. |
| GO:0051260 protein homooligomerization | IDA PMID:30279485 RIP2 filament formation is required for NOD2 dependent NF-ΞΊB... | ACCEPT | Summary: Protein homo-oligomerization (filament, CORE-adjacent). Reason: RIPK2 CARD oligomerizes into filaments required for NOD2 signaling (PMID:30279485). Supporting Evidence: PMID:30279485 the importance of RIP2 polymerization for the |
| GO:0051260 protein homooligomerization | IDA PMID:30478312 Structural basis of RIP2 activation and signaling. | ACCEPT | Summary: Protein homo-oligomerization (filament). Reason: RIP2-CARD forms oligomeric structures upon NOD1/NOD2 stimulation (PMID:30478312). Supporting Evidence: PMID:30478312 critical for signal propagation of the |
| GO:0070427 nucleotide-binding oligomerization domain containing 1 signaling pathway | IDA PMID:29452636 Disruption of XIAP-RIP2 Association Blocks NOD2-Mediated Inf... | ACCEPT | Summary: NOD1 signaling pathway (CORE). Reason: RIPK2 is the essential adaptor of NOD1 signaling. |
| GO:0070427 nucleotide-binding oligomerization domain containing 1 signaling pathway | IDA PMID:30279485 RIP2 filament formation is required for NOD2 dependent NF-ΞΊB... | ACCEPT | Summary: NOD1 signaling pathway (CORE). Reason: RIP2 filament formation is required for NOD-dependent signaling (PMID:30279485). Supporting Evidence: PMID:30279485 the importance of RIP2 polymerization for the |
| GO:0070427 nucleotide-binding oligomerization domain containing 1 signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: NOD1 signaling pathway (IEA). Reason: Consistent core role. |
| GO:0070431 nucleotide-binding oligomerization domain containing 2 signaling pathway | IDA PMID:16824733 Identification of a regulatory autophosphorylation site in t... | ACCEPT | Summary: NOD2 signaling pathway (CORE). Reason: RIPK2 is the obligate CARD adaptor of NOD2 signaling, recruited by NOD2 2CARD and required for NF-kB/MAPK output. |
| GO:0070431 nucleotide-binding oligomerization domain containing 2 signaling pathway | IDA PMID:17355968 The NOD2-RICK complex signals from the plasma membrane. | ACCEPT | Summary: NOD2 signaling pathway (CORE). Reason: RIPK2 is the obligate CARD adaptor of NOD2 signaling, recruited by NOD2 2CARD and required for NF-kB/MAPK output. |
| GO:0070431 nucleotide-binding oligomerization domain containing 2 signaling pathway | IDA PMID:17562858 Coordinated regulation of Toll-like receptor and NOD2 signal... | ACCEPT | Summary: NOD2 signaling pathway (CORE). Reason: RIPK2 is the obligate CARD adaptor of NOD2 signaling, recruited by NOD2 2CARD and required for NF-kB/MAPK output. |
| GO:0070431 nucleotide-binding oligomerization domain containing 2 signaling pathway | IDA PMID:23806334 OTULIN restricts Met1-linked ubiquitination to control innat... | ACCEPT | Summary: NOD2 signaling pathway (CORE). Reason: RIPK2 is the obligate CARD adaptor of NOD2 signaling, recruited by NOD2 2CARD and required for NF-kB/MAPK output. Supporting Evidence: PMID:23806334 RIPK2 as the predominant NOD2-regulated |
| GO:0070431 nucleotide-binding oligomerization domain containing 2 signaling pathway | IDA PMID:28545134 Structures of the inactive and active states of RIP2 kinase ... | ACCEPT | Summary: NOD2 signaling pathway (CORE). Reason: RIPK2 is the obligate CARD adaptor of NOD2 signaling, recruited by NOD2 2CARD and required for NF-kB/MAPK output. Supporting Evidence: PMID:28545134 recruitment of adaptor kinase RIP2 |
| GO:0070431 nucleotide-binding oligomerization domain containing 2 signaling pathway | IDA PMID:29452636 Disruption of XIAP-RIP2 Association Blocks NOD2-Mediated Inf... | ACCEPT | Summary: NOD2 signaling pathway (CORE). Reason: RIPK2 is the obligate CARD adaptor of NOD2 signaling, recruited by NOD2 2CARD and required for NF-kB/MAPK output. |
| GO:0070431 nucleotide-binding oligomerization domain containing 2 signaling pathway | IDA PMID:30026309 Small molecule inhibitors reveal an indispensable scaffoldin... | ACCEPT | Summary: NOD2 signaling pathway (CORE). Reason: RIPK2 is the obligate CARD adaptor of NOD2 signaling, recruited by NOD2 2CARD and required for NF-kB/MAPK output. Supporting Evidence: PMID:30026309 RIPK2 mediates inflammatory signaling by the bacteria-sensing receptors NOD1 and |
| GO:0070431 nucleotide-binding oligomerization domain containing 2 signaling pathway | IDA PMID:30279485 RIP2 filament formation is required for NOD2 dependent NF-ΞΊB... | ACCEPT | Summary: NOD2 signaling pathway (CORE). Reason: RIPK2 is the obligate CARD adaptor of NOD2 signaling, recruited by NOD2 2CARD and required for NF-kB/MAPK output. Supporting Evidence: PMID:30279485 the importance of RIP2 polymerization for the |
| GO:0070431 nucleotide-binding oligomerization domain containing 2 signaling pathway | IDA PMID:30478312 Structural basis of RIP2 activation and signaling. | ACCEPT | Summary: NOD2 signaling pathway (CORE). Reason: RIPK2 is the obligate CARD adaptor of NOD2 signaling, recruited by NOD2 2CARD and required for NF-kB/MAPK output. Supporting Evidence: PMID:30478312 critical for signal propagation of the |
| GO:0070431 nucleotide-binding oligomerization domain containing 2 signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: NOD2 signaling pathway (IEA). Reason: Consistent core role. |
| GO:0071225 cellular response to muramyl dipeptide | IDA PMID:21887730 Control of NOD2 and Rip2-dependent innate immune activation ... | ACCEPT | Summary: Cellular response to muramyl dipeptide (CORE). Reason: RIPK2 transduces the NOD2 response to the bacterial ligand MDP (PMID:21887730). Supporting Evidence: PMID:21887730 GEF-H1 connects tyrosine kinase function to NOD-like receptor |
| GO:0071225 cellular response to muramyl dipeptide | IEA GO_REF:0000120 | ACCEPT | Summary: Cellular response to muramyl dipeptide (IEA). Reason: Consistent core role. |
| GO:0089720 caspase binding | IPI PMID:11432859 Cop, a caspase recruitment domain-containing protein and inh... | KEEP AS NON CORE | Summary: Caspase-1 (CARD) binding. Reason: RIPK2/CARDIAK binds procaspase-1 via CARD-CARD (original CARDIAK characterization); a documented interaction but secondary to the core NF-kB adaptor role. |
| GO:0089720 caspase binding | IPI PMID:11536016 Regulation of IL-1beta generation by Pseudo-ICE and ICEBERG,... | KEEP AS NON CORE | Summary: Caspase-1 (CARD) binding. Reason: RIPK2/CARDIAK binds procaspase-1 via CARD-CARD (original CARDIAK characterization); a documented interaction but secondary to the core NF-kB adaptor role. |
| GO:0089720 caspase binding | IPI PMID:15383541 INCA, a novel human caspase recruitment domain protein that ... | KEEP AS NON CORE | Summary: Caspase-1 (CARD) binding. Reason: RIPK2/CARDIAK binds procaspase-1 via CARD-CARD (original CARDIAK characterization); a documented interaction but secondary to the core NF-kB adaptor role. |
| GO:0106310 protein serine kinase activity | EXP PMID:16824733 Identification of a regulatory autophosphorylation site in t... | KEEP AS NON CORE | Summary: Protein serine kinase activity (EXP, Ser176 autophosphorylation). Reason: Bona fide autokinase activity (Ser176 autophosphorylation, PMID:16824733). Retained as real; non-core because catalysis is dispensable for NOD1/NOD2 signaling output. Supporting Evidence: PMID:16824733 S176 is a regulatory autophosphorylation site |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Protein serine kinase activity (IEA/Rhea). Reason: Real activity; non-core. |
| GO:0140895 cell surface toll-like receptor signaling pathway | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Cell surface TLR signaling (IEA). Reason: RIPK2 acts downstream of surface TLR2/4 (PMID:11894098); secondary to core NOD role. |
| GO:1902523 positive regulation of protein K63-linked ubiquitination | IDA PMID:17562858 Coordinated regulation of Toll-like receptor and NOD2 signal... | ACCEPT | Summary: Positive regulation of protein K63-linked ubiquitination (CORE). Reason: NOD2/RIPK2 drives formation of K63-linked polyubiquitin chains (on RIPK2 itself and on NEMO) that recruit the TAK1 and IKK complexes (PMID:17562858). Central to the ubiquitin-scaffold function. |
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Download this section (compressed HTML)Q: Is RIPK2 tyrosine autophosphorylation at Tyr474 required for NOD2 signaling in a way distinct from catalysis per se, given that kinase-dead K47R and D146N mutants (which cannot autophosphorylate) nonetheless fully restore NOD2 signaling?
Experiment: Reconstitute RIPK2-knockout cells with wild-type, kinase-dead (K47R, D146N), and ubiquitination-site (K209R) RIPK2 and quantify NOD2-induced RIPK2 ubiquitination, TAK1/IKK recruitment, and NF-kappaB/cytokine output, to cleanly separate the catalytic contribution from the scaffold/ubiquitination contribution.
Experiment: Define the minimal determinants of the XIAP-BIR2 binding surface on the RIPK2 kinase N-lobe (beta2-beta3 loop) by structure-guided mutagenesis, and test whether disrupting XIAP binding without perturbing catalysis abolishes NOD2 signaling.
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