Affinage

RIPK2

Receptor-interacting serine/threonine-protein kinase 2 · UniProt O43353

Length
540 aa
Mass
61.2 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RIPK2 (RICK/CARDIAK/CARD3) is a dual-domain serine/threonine kinase with an N-terminal kinase domain and a C-terminal CARD that functions as the obligate adaptor kinase coupling the cytosolic pattern-recognition receptors NOD1 and NOD2 to NF-κB and MAPK-driven pro-inflammatory cytokine production (PMID:17277144, PMID:10880512). Recruitment occurs through homotypic CARD-CARD engagement that is critically dependent on a set of acidic residues on the NOD1 CARD pairing with basic residues on the RIPK2 CARD (PMID:17054981), and NOD2 directs RIPK2 to the plasma membrane where signaling is optimal—a step disrupted by the Crohn's disease-associated NOD2 1007FS mutant (PMID:17355968). Once recruited, RIPK2 propagates signaling primarily as a scaffold rather than a catalyst: K63-linked polyubiquitination recruits TAK1 to activate the IKK complex (PMID:18079694), and the interaction between RIPK2 and the E3 ligase XIAP—mediated by the β2-β3 loop of the kinase N-lobe adjacent to the ATP pocket—is mechanistically more important than catalytic activity for productive NOD signaling, explaining why ATP-competitive and type II kinase inhibitors act largely by sterically blocking the RIPK2-XIAP interface (PMID:30026309, PMID:26320862). RIPK2 also undergoes autophosphorylation at Y474 and S176 that governs assembly of higher-order detergent-insoluble speck-like complexes, a process restrained by XIAP-mediated ubiquitination (PMID:31350258). The pathway connects upstream to oligomerization-induced NF-κB activation via the intermediate region and IKKγ/NEMO (PMID:10880512), and RIPK2 additionally operates downstream of TLR2/3/4 and IL-1/IL-18 receptors and in T-cell receptor signaling required for IL-2 production and TH1 differentiation (PMID:11894098). RIPK2 abundance and activity are tuned by an opposing set of writers and erasers acting on its ubiquitination and phosphorylation—including K48-ubiquitin control of stability, the deubiquitinases YOD1 and MYSM1, and the K63-promoting ligase-associated factor N4BP3 (PMID:32954645, PMID:39333628, PMID:39746943, PMID:39420190)—and the kinase is targeted for inactivation by pathogen-derived enzymes including Yersinia YopJ acetylation of its activation loop and gingipain (Kgp) proteolysis (PMID:22520462, PMID:22685397). Beyond canonical innate immunity, RIPK2 drives cancer metastasis through a noncanonical pathway in which it binds and activates MKK7 to stabilize c-Myc (PMID:35115556).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 High

    Established RIPK2's basic architecture and first signaling outputs, framing it as a CARD-containing kinase linking death/inflammatory adaptors to NF-κB, JNK, and caspase activation.

    Evidence Co-IP, overexpression, dominant-negative K38M mutagenesis, and NF-κB/JNK reporter and apoptosis assays identifying interactions with CLARP/caspase-8, caspase-1, and TRAFs

    PMID:9575181 PMID:9705938

    Open questions at the time
    • Overexpression-based; physiological receptor context not yet defined
    • Whether kinase activity or scaffolding drives each output unresolved
  2. 2000 High

    Defined an induced-proximity model whereby RIPK2 oligomerization engages IKKγ/NEMO through its intermediate region, not its kinase domain, to activate NF-κB downstream of NOD1.

    Evidence Co-IP, enforced oligomerization, dominant-negative IKKγ, and NF-κB reporter assays

    PMID:10880512

    Open questions at the time
    • How endogenous receptor engagement triggers oligomerization not shown
    • Role of ubiquitination in IKK recruitment not yet addressed
  3. 2002 High

    Genetically placed RIPK2 downstream of multiple immune receptors, showing it is required for innate responses (TLR2/3/4, NOD, IL-1/IL-18) and adaptive T-cell function.

    Evidence Rip2-deficient mouse cells with recruitment Co-IP, cytokine, NF-κB, T-cell proliferation and TH1 differentiation readouts

    PMID:11894098

    Open questions at the time
    • Breadth of TLR involvement later narrowed by cleaner agonist studies
    • Direct versus indirect roles in adaptive immunity not fully separated
  4. 2005 High

    Provided in vitro enzymatic characterization, identifying substrates and the residue conferring pyridinyl imidazole inhibitor sensitivity.

    Evidence In vitro autophosphorylation and substrate (MBP, histone H3) kinase assays with Km determination and conserved threonine mutant analysis

    PMID:15724446

    Open questions at the time
    • Physiological relevance of MBP/H3 as substrates unestablished
    • In vitro substrates may not reflect in-cell targets
  5. 2006 High

    Resolved the structural basis of NOD1-RIPK2 CARD-CARD recognition, identifying the electrostatic interface essential for downstream signaling.

    Evidence NMR structure of NOD1 CARD with mutagenesis of acidic/basic residue pairs, Co-IP, and NF-κB reporter validation

    PMID:17054981

    Open questions at the time
    • NOD2 CARD interface not structurally resolved here
    • Affinity and stoichiometry of the assembled complex not quantified
  6. 2007 High

    Defined the central signaling steps: clean genetic placement downstream of NOD1/NOD2, K63-ubiquitination at K209 recruiting TAK1, and NOD2-driven membrane recruitment as the site of optimal signaling.

    Evidence RICK-null macrophages, K209 mutagenesis and ubiquitination assays with TAK1-deficient cells, and membrane-targeting/fractionation constructs including the NOD2 1007FS mutant

    PMID:17277144 PMID:17355968 PMID:18079694

    Open questions at the time
    • K209 ubiquitination later not detected at endogenous levels
    • E3 ligase responsible for K63 chains not identified at this stage
  7. 2012 High

    Revealed RIPK2 as a target of bacterial immune-evasion enzymes that inactivate it by distinct mechanisms.

    Evidence In-cell acetylation assay with catalytically dead YopJ control, and cell-free proteolysis with Kgp-specific inhibitor and isogenic Kgp-deficient P. gingivalis

    PMID:22520462 PMID:22685397

    Open questions at the time
    • RIPK2 acetylation and cleavage sites not fully mapped
    • Consequences for higher-order complex assembly not examined
  8. 2015 High

    Dissected the kinase-activity-versus-scaffold question with structures and selective inhibitors, showing type II inhibitors block autophosphorylation, ubiquitination, and NF-κB signaling while kinase activity timing tunes productive responses.

    Evidence First RIPK2 crystal structure with ponatinib, type I vs type II inhibitor profiling, and the selective inhibitor WEHI-345 with ubiquitylation kinetics and in vivo/EAE readouts

    PMID:25778803 PMID:26320862

    Open questions at the time
    • Molecular reason inhibitors block ubiquitination not yet defined (resolved later)
    • Distinction between catalytic and non-catalytic inhibitor effects unresolved here
  9. 2015 Medium

    Extended the proteolytic-inactivation theme to viral infection, implicating HIV-1 protease cleavage of RIPK2 as a candidate immune-evasion strategy.

    Evidence HIV-1 infection of T cells with stage-specific protease/RT/integrase inhibitors and Co-IP of the related RIPK1/RIPK3 complex

    PMID:26297639

    Open questions at the time
    • RIPK2 cleavage site not mapped
    • Functional consequence for RIPK2 signaling not directly demonstrated
  10. 2018 High

    Resolved the inhibitor mechanism by mapping the XIAP-binding site to the β2-β3 loop near the ATP pocket, establishing that inhibitors act by blocking the RIPK2-XIAP interaction rather than catalysis.

    Evidence XIAP binding mapping, site-directed mutagenesis, kinase assays, Co-IP, and in vivo NOD2 signaling, plus a co-crystal structure of RIPK2 with the activation-loop inhibitor CSR35 defining a Lys169 ionic contact

    PMID:29409752 PMID:30026309

    Open questions at the time
    • Stoichiometry and dynamics of the RIPK2-XIAP complex not fully defined
    • How XIAP ubiquitination is coupled to TAK1/IKK recruitment not fully resolved
  11. 2019 High

    Connected RIPK2 autophosphorylation to higher-order assembly, showing Y474/S176 phosphorylation drives speck-like complex formation that XIAP-mediated ubiquitination restrains.

    Evidence Detergent fractionation with Y474/S176 and XIAP-ubiquitylation-site mutagenesis in bacterial infection models

    PMID:31350258

    Open questions at the time
    • Functional output of speck assembly versus signaling not fully separated
    • Structure of the higher-order complex unknown
  12. 2020 High

    Refined the ubiquitin code at endogenous levels, distinguishing K48 control of stability from a separate XIAP-binding regulatory region, and identifying the MYSM1-PP2A axis as an eraser of RIPK2 ubiquitination and S176 phosphorylation.

    Evidence CRISPR FLAG-RIPK2 knock-in mice with MS-based PTM mapping and mutagenesis; MYSM1-PP2A-RIPK2 Co-IP with S176 phosphomimetic/phospho-dead mutants in an OA model

    PMID:32954645 PMID:39746943

    Open questions at the time
    • Identity of the K48 ligase(s) controlling stability not pinned down
    • Reconciliation with prior K209 ubiquitination model only partially addressed
  13. 2022 High

    Defined a noncanonical, oncogenic RIPK2 pathway in which it binds and activates MKK7 to phosphorylate and stabilize c-Myc, driving metastasis independent of NOD/NF-κB.

    Evidence Co-IP, multi-level proteomics, RIPK2 knockout, c-Myc-S62 phosphorylation assays, inhibitors, and in vivo metastasis models

    PMID:35115556

    Open questions at the time
    • How RIPK2 selects MKK7 over canonical effectors not defined
    • Relationship between scaffolding and catalytic requirements in this pathway unclear
  14. 2024 Medium

    Expanded the network of opposing ubiquitin enzymes tuning RIPK2 abundance and activity, with YOD1 protecting RIPK2 from K48-degradation and N4BP3 promoting activating K63 chains.

    Evidence YOD1-deficient mice with K48-linkage assays and DSS colitis; N4BP3 Co-IP, K63-ubiquitination assays, siRNA knockdown, and phosphoprotein readouts

    PMID:39333628 PMID:39420190

    Open questions at the time
    • Direct enzyme-substrate kinetics not established for N4BP3
    • Whether YOD1 and XIAP act on overlapping sites unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RIPK2's canonical scaffolding/ubiquitination machinery is repurposed in its noncanonical oncogenic and inflammasome-modulating roles, and how the full set of writer/eraser enzymes is coordinated in vivo, remains unresolved.
  • No unified model linking PTM state to choice between NOD/NF-κB, MKK7/c-Myc, and caspase-1 modulation
  • Structure of the assembled NOD-RIPK2-XIAP-TAK1 signaling node not determined
  • Relative in vivo contribution of catalytic versus scaffold functions across tissues unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0060090 molecular adaptor activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3
Partners
IKBKGMAP2K7NOD1NOD2PRKCITAK1TRAF6XIAP

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 RICK (RIPK2) was identified as a novel serine-threonine kinase containing an N-terminal kinase domain and C-terminal CARD. It physically interacts with CLARP (a caspase-like molecule binding FADD and caspase-8), and its expression promoted caspase-8 activation and apoptosis induced by Fas ligand, FADD, and caspase-8. A kinase-dead mutant (K38M) functioned as a dominant-negative inhibitor of CD95-mediated apoptosis, demonstrating both kinase domain and CARD are required for pro-apoptotic function. Co-immunoprecipitation, overexpression, dominant-negative mutagenesis, apoptosis assays The Journal of biological chemistry High 9575181
1998 CARDIAK (RIPK2) was identified as a RIP-like kinase containing a CARD that specifically interacts with caspase-1 via CARD-CARD interaction. This interaction correlated with processing of pro-caspase-1 to the active p20 subunit. Overexpression activated both NF-κB and JNK, and CARDIAK interacted with TRAF-1 and TRAF-2; dominant-negative TRAF-2 inhibited CARDIAK-induced NF-κB activation. Co-immunoprecipitation, overexpression, NF-κB/JNK reporter assays, dominant-negative TRAF-2 Current biology : CB High 9705938
2000 RICK (RIPK2) was shown to interact with IKKγ (NEMO) via its intermediate region (not its kinase domain), linking NOD1/Nod1-mediated proximity signaling to IKK activation. Enforced oligomerization of RICK was sufficient to activate NF-κB, and a mutant IKKγ deficient in IKKα/β binding blocked RICK-induced NF-κB activation. This defined an induced-proximity model for NF-κB activation downstream of Nod1. Co-immunoprecipitation, enforced oligomerization, dominant-negative IKKγ, NF-κB reporter assays The Journal of biological chemistry High 10880512
2002 Rip2 (RIPK2) was recruited to TLR2 signaling complexes after ligand stimulation. Rip2-deficient cells showed reduced cytokine production upon TLR2/3/4 stimulation but not TLR9, indicating Rip2 acts downstream of TLR2/3/4 but not TLR9. Rip2-deficient cells were also hyporesponsive to IL-1 and IL-18 receptor signaling and to Nod proteins. Rip2-deficient T cells showed severely reduced NF-κB activation, IL-2 production, proliferation on TCR engagement, and impaired TH1 differentiation. Rip2-deficient mouse cells, co-immunoprecipitation (recruitment to TLR2 complex), cytokine assays, NF-κB activation assays Nature High 11894098
2006 NMR solution structure of the NOD1 CARD was determined. Mutagenesis revealed that CARD-CARD interaction between NOD1 and RICK is critically dependent on three acidic residues on NOD1 CARD and three basic residues on RICK CARD, indicating a strong electrostatic component to the NOD1-RICK interaction essential for downstream NF-κB signaling. NMR structure determination, site-directed mutagenesis, co-immunoprecipitation from cell lysates, NF-κB reporter assay Journal of molecular biology High 17054981
2007 RICK (RIPK2) is required for innate immune responses to Nod1 and Nod2 agonists but not for responses to highly purified TLR agonists (LPS, etc.) in macrophages and mice. RICK-null macrophages were defective in Nod1/Nod2-mediated NF-κB activation and cytokine production, while TLR-mediated responses were intact. This definitively placed RICK downstream of Nod1/Nod2 but not TLRs. RICK-deficient mouse macrophages, cytokine ELISA, NF-κB activation assays, in vivo infection models Journal of immunology (Baltimore, Md. : 1950) High 17277144
2007 RICK undergoes K63-linked polyubiquitination at lysine 209 (K209) in its kinase domain upon Nod1 or Nod2 stimulation or RICK oligomerization. This ubiquitination is essential for IKK activation and cytokine/chemokine secretion but does not require RICK kinase activity or alter RICK-NEMO interaction. K63-polyubiquitinated RICK recruits TAK1, linking TAK1 to IKK complexes as a critical step in Nod-mediated NF-κB activation. Ubiquitination assays, K209 mutagenesis, co-immunoprecipitation, cytokine secretion assays, TAK1-deficient cells The EMBO journal High 18079694
2007 NOD2 promotes the membrane recruitment of RICK; membrane-anchored NOD2 recruits RICK to the plasma membrane where RICK signaling is optimal. Artificial attachment of RICK at the plasma membrane caused constitutive strong NF-κB activation and IL-8 secretion. The NOD2 1007FS Crohn's disease mutant was unable to signal from the plasma membrane, correlating with impaired RICK recruitment. Subcellular fractionation, membrane targeting constructs, immunofluorescence, NF-κB reporter assays, IL-8 secretion measurement The Journal of biological chemistry High 17355968
2012 The Yersinia pseudotuberculosis effector YopJ acetylates critical sites in the activation loops of RICK and TAK1 kinases, blocking their activity. The catalytically inactive YopJ(C172A) mutant failed to acetylate RICK or TAK1 and could not subvert Nod2 signaling. YopJ acetylation of RICK also decreased the affinity of Nod2 for RICK and concurrently redirected Nod2 to interact with and activate caspase-1. In-cell acetylation assay, catalytically inactive mutant YopJ, co-immunoprecipitation, caspase-1 activation assay, IL-1β measurement Cell host & microbe High 22520462
2012 P. gingivalis infection of human aortic endothelial cells caused rapid cleavage of RIPK2. Cleavage was not observed with apoptotic stimuli or TLR/NOD agonists, was inhibited by a lysine-specific gingipain (Kgp) inhibitor, and was absent with an isogenic Kgp-deficient P. gingivalis mutant. Direct proteolysis of RIPK2 by P. gingivalis was confirmed in a cell-free system, defining Kgp as the protease responsible. Cell-free proteolysis assay, Kgp-specific inhibitor, isogenic Kgp-deficient mutant, immunoblotting PLoS pathogens High 22685397
2015 RIPK2 kinase activity is dispensable for NF-κB activation per se, but type II kinase inhibitors (ponatinib, regorafenib) that displace the activation segment block RIPK2 autophosphorylation, RIPK2 ubiquitination, and inflammatory NF-κB signaling. Type I (ATP-competitive) inhibition was only poorly effective. A crystal structure of RIPK2 bound to ponatinib was determined, revealing the activation segment conformation and an allosteric site. Crystal structure (first RIPK2 crystal structure), kinase inhibitor profiling, autophosphorylation assay, ubiquitination assay, NF-κB reporter, monocyte cytokine production Chemistry & biology High 26320862
2015 HIV-1 protease cleaves RIPK2 during infection of T cells. Cleavage was prevented by HIV-1 protease inhibitor but not by inhibitors of RT or integrase. Cleavage of RIPK1 (which was identified at a defined PR cleavage site) disrupted RIPK1/RIPK3 complex formation and NF-κB induction; analogous cleavage of RIPK2 is proposed as a viral immune evasion strategy. HIV-1 infection of T cells, stage-specific inhibitors, co-immunoprecipitation (RIPK1/RIPK3 complex), NF-κB assay, site mutagenesis (RIPK1 cleavage site) Retrovirology Medium 26297639
2015 WEHI-345, a selective RIPK2 kinase inhibitor, delays but does not abolish RIPK2 ubiquitylation and NF-κB activation downstream of NOD engagement. Despite only delaying NF-κB activation, WEHI-345 prevents cytokine production in vitro and in vivo, demonstrating that kinase activity timing is critical for productive immune responses and that RIPK2 kinase activity is required for proper NOD signaling. Selective kinase inhibitor, ubiquitylation kinetics assay, NF-κB activation kinetics, cytokine production assay in vitro/in vivo, EAE model Nature communications High 25778803
2018 RIPK2 kinase activity is dispensable for NOD2 inflammatory signaling. Instead, kinase inhibitors function by antagonizing the XIAP-binding interaction. The XIAP binding site on RIPK2 was mapped to the loop between β2 and β3 of the N-lobe of the kinase domain, in close proximity to the ATP-binding pocket. Inhibitor binding to the ATP pocket sterically blocks the RIPK2-XIAP interaction, preventing XIAP-mediated ubiquitination of RIPK2 and downstream NOD2 signaling. XIAP binding mapping, site-directed mutagenesis, kinase activity assays, co-immunoprecipitation, in vivo NOD2 signaling assays The EMBO journal High 30026309
2019 RIPK2 forms detergent-insoluble, higher-order molecular complexes (speck-like structures) in the cytosol upon infection with invasive enteropathogenic bacteria. Complex formation required RIPK2 autophosphorylation at Y474, was influenced by S176 phosphorylation, and depended on the CARD of NOD1 or NOD2. XIAP counteracts RIPK2 complex formation; mutation of XIAP ubiquitylation sites on RIPK2 enhanced complex formation, identifying XIAP-mediated ubiquitination as a brake on RIPK2 aggregation. Detergent fractionation, autophosphorylation site mutagenesis (Y474, S176), XIAP ubiquitylation site mutagenesis, bacterial infection model Life science alliance High 31350258
2020 A regulatory region on RIPK2 (distinct from K209) is required for XIAP binding and downstream NOD signaling. Using endogenous FLAG-RIPK2 knock-in mice and site-directed mutagenesis, K48-linked ubiquitination at specific residues was found to control RIPK2 stability, while distinct sites govern XIAP binding and signaling. K209 ubiquitination was not detected during NOD2 signaling at endogenous levels, contrasting with earlier overexpression data. CRISPR/Cas9 FLAG-RIPK2 knock-in mice, site-directed mutagenesis, mass spectrometry-based post-translational modification mapping, NOD2 signaling assays EMBO reports High 32954645
2021 ATG16L1 physically binds the RICK/RIPK2 kinase domain and negatively regulates TLR2-mediated NF-κB activation and pro-inflammatory cytokine responses by inhibiting the interaction between TLR2 and RICK/RIPK2. ATG16L1 binding suppresses NF-κB activation by down-regulating RICK polyubiquitination. Co-immunoprecipitation in HEK293 cells and primary human dendritic cells, NF-κB activation assays, cytokine measurement International immunology Medium 32909611
2022 RIPK2 stabilizes c-Myc and promotes prostate cancer metastasis by binding to and activating MKK7, which was identified as a direct c-Myc-S62 kinase. This defines a noncanonical RIPK2/MKK7/c-Myc pathway distinct from the canonical NOD/NF-κB pathway. RIPK2 inhibition inactivated MKK7 and c-Myc-S62 phosphorylation. Co-immunoprecipitation, multi-level proteomics, RIPK2 knockout, phosphorylation assays (c-Myc S62), kinase inhibitors, in vivo metastasis models Nature communications High 35115556
2014 NOD2 activation results in increased IRF4 expression, which then binds TRAF6 and RICK. IRF4 binding leads to inhibition of K63-linked polyubiquitination of both TRAF6 and RICK, thereby downregulating NF-κB activation. This defines a negative feedback mechanism where NOD2 activation ultimately suppresses TLR-mediated inflammatory responses. Co-immunoprecipitation (IRF4 binding to TRAF6 and RICK), ubiquitination assays (K63-linkage), in vivo colitis model with MDP/IRF4 treatment Mucosal immunology Medium 24670424
2005 RIP2/RICK/CARDIAK is a direct substrate for pyridinyl imidazole p38 MAPK inhibitors (SB220025, SB203580, PD169316) in vitro, with inhibition at concentrations comparable to p38 inhibition. RIP2 autophosphorylation and its ability to phosphorylate myelin basic protein (Km=2.1 μM) and histone H3 (Km=0.65 μM) were identified as new substrates. A conserved threonine in the RIP2 kinase domain (equivalent to p38) was required for inhibitor sensitivity. In vitro kinase autophosphorylation assay, substrate phosphorylation assay (MBP, histone H3), Km determination, threonine mutant analysis Molecular and cellular biochemistry High 15724446
2003 CARD6 specifically binds Nod1 (CARD4) and Cardiak (RIPK2) by immunoprecipitation but not other CARD family proteins, and acts as a selective modulator suppressing NF-κB induction by Nod1 or Cardiak. Cardiak and Nod1 had opposing effects on CARD6 phosphorylation and expression. CARD6 did not interfere with CARD-containing adaptor Bcl10 or TNF-α-induced NF-κB nor with caspase-1-dependent IL-1β secretion. Co-immunoprecipitation, NF-κB reporter transfection assay, phosphorylation analysis The Journal of biological chemistry Medium 12775719
2003 RICK activates NF-κB through its intermediate domain (not kinase activity, as both kinase-active and kinase-inactive forms activated NF-κB) and this NF-κB activation potently blocks HCMV replication in human fibroblasts. A stable IκB inhibitor reversed RICK's anti-HCMV effect. RICK expression synergized with HCMV infection in inducing IFN-β, which was identified as a downstream component of the RICK inhibitory pathway. Kinase-active and kinase-dead RICK overexpression, stable IκB inhibitor, supernatant IFN-β transfer experiments, viral replication assay The Journal of biological chemistry Medium 14670961
2003 The CARD of RICK folds as an α-helical Greek key structure with marginal stability (ΔG = 3.0 kcal/mol). Equilibrium folding follows a two-state mechanism, but unfolding and refolding kinetics are complex with at least three non-native conformations and kinetically trapped species, likely involving parallel folding pathways rather than prolyl isomerism. Equilibrium and stopped-flow kinetic folding spectroscopy, chemical denaturation, guanidinium/salt titrations Biochemistry Medium 12755636
2013 NOD2 activation by PGN in oligodendrocyte precursor cells (OPCs) leads to RIPK2 recruitment and phosphorylation of RIPK2, followed by phosphorylation of neuronal nitric oxide synthase (nNOS). This increases NOS activity and NO accumulation leading to mitochondrial respiratory enzyme inhibition (complex I and IV), reduced mitochondrial membrane potential, and cytochrome-C release. Intracerebral PGN injection in rats caused CNS demyelination. OPC cultures, NOD2 ligand stimulation, RIPK2 phosphorylation assay, nNOS phosphorylation, NOS activity assay, specific inhibitors (7-NI vs L-canavanine), mitochondrial function assays, in vivo rat injection Journal of neuroimmunology Medium 24169446
2020 MYSM1 deubiquitinates RIPK2 and dephosphorylates RIPK2 at S176 by recruiting protein phosphatase 2A (PP2A) to RIPK2. This attenuates NF-κB and MAPK signaling. The Ripk2S176D (phosphomimetic) mutation accelerated OA pathogenesis, while Ripk2 silencing or Ripk2S176A mutation deactivated NF-κB and MAPK pathways and counteracted the role of MYSM1. Co-immunoprecipitation (MYSM1-PP2A-RIPK2 complex), S176 phosphomimetic and phospho-dead mutagenesis in mice, deubiquitination assays, NF-κB/MAPK signaling assays, in vivo OA mouse model Bone research High 39746943
2024 YOD1, a deubiquitinating enzyme, inhibits K48-linked polyubiquitination of RIPK2, preventing its proteasomal degradation and thereby increasing RIPK2 abundance to enhance NOD2 signaling. YOD1-deficient mice show increased susceptibility to DSS-induced colitis, and the protective function of the NOD2 ligand MDP in experimental colitis was abolished in YOD1-deficient mice. YOD1-deficient mice, bone marrow transplantation, K48-ubiquitination assays, NOD2 signaling assays in macrophages, DSS colitis model EMBO reports High 39333628
2024 N4BP3 interacts with RIPK2 (demonstrated by co-immunoprecipitation) and promotes K63-linked ubiquitination of RIPK2, further promoting the NOD2-MAPK/NF-κB pathway and increasing pro-inflammatory cytokine release. N4BP3 knockdown reduced MDP-induced inflammatory cytokines and NOD2-pathway phosphoproteins (ERK1/2, JNK, P38, NF-κB p65). Co-immunoprecipitation, K63-ubiquitination assay, siRNA knockdown, MDP stimulation, phosphoprotein immunoblotting, in vivo DSS colitis Cell death discovery Medium 39420190
2025 RIPK2 promotes colorectal cancer metastasis through a mechanism involving K63-linked ubiquitination of RIPK2 (triggered by MDP/NOD2 activation), and RIPK2 interaction with the E3 ubiquitin ligase ITCH which balances K63-ubiquitination of RIPK2 with K48-ubiquitination of YAP (leading to YAP degradation). RIPK2 knockdown increased ITCH-mediated K48-ubiquitination and degradation of YAP. GSK583 (RIPK2 inhibitor) disrupted YAP stability. Co-immunoprecipitation (RIPK2-ITCH interaction), ubiquitination linkage assays (K63/K48), RIPK2 knockdown, pharmacological inhibition, in vivo xenograft and metastasis models, proteomic analysis Cell death & disease Medium 40185717
2022 RIPK2 interacts with PRKCI (as shown by co-immunoprecipitation and immunofluorescence) to enhance phosphorylation of NF-κB, JNK, and ERK downstream. RIPK2 knockout suppressed subcutaneous tumor growth, liver metastasis, inhibited autophagosome formation, and increased ROS production and apoptosis in pancreatic cancer cells. Co-immunoprecipitation, immunofluorescence, RIPK2 knockout, phosphorylation immunoblotting, in vivo xenograft and metastasis models Molecular medicine (Cambridge, Mass.) Medium 37016317
2022 Card9 inhibits NLRP3 inflammasome activation in macrophages by recruiting Ripk2. Ripk2 competitively binds Caspase-1, preventing the normal ASC-Caspase-1 interaction required for NLRP3 inflammasome assembly. Overexpression of Ripk2 alleviated septic intestinal injury caused by Card9 deficiency. Co-immunoprecipitation (Card9-Ripk2; Ripk2-Caspase-1 vs ASC-Caspase-1 competition), Card9-knockout mice, NLRP3 inflammasome activation assay, Ripk2 overexpression rescue Cell death & disease Medium 35618701
2018 A co-crystal structure of RIPK2 bound to the activation loop targeting inhibitor CSR35 revealed a resolved activation loop with an ionic interaction between the inhibitor carboxylic acid and the side-chain of Lys169 in the activation loop, providing structural basis for activation-loop-targeting type II inhibitor strategy and >10-fold selectivity over VEGFR2. Co-crystal structure of RIPK2-CSR35 complex, biochemical kinase inhibition assay Bioorganic & medicinal chemistry letters High 29409752

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 727 11894098
2000 An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways. The Journal of biological chemistry 444 10880512
2007 A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. The EMBO journal 430 18079694
2007 RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. Journal of immunology (Baltimore, Md. : 1950) 426 17277144
1998 Identification of CARDIAK, a RIP-like kinase that associates with caspase-1. Current biology : CB 269 9705938
1998 RICK, a novel protein kinase containing a caspase recruitment domain, interacts with CLARP and regulates CD95-mediated apoptosis. The Journal of biological chemistry 217 9575181
2004 Inhibition of p38 MAP kinase- and RICK/NF-kappaB-signaling suppresses inflammatory bowel disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 194 15289440
2020 Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2. Communications biology 177 32198438
2007 Nod1/RICK and TLR signaling regulate chemokine and antimicrobial innate immune responses in mesothelial cells. Journal of immunology (Baltimore, Md. : 1950) 154 17579072
2020 Fusobacterium nucleatum Promotes Metastasis in Colorectal Cancer by Activating Autophagy Signaling via the Upregulation of CARD3 Expression. Theranostics 152 31903123
2005 Inhibition of RICK/nuclear factor-kappaB and p38 signaling attenuates the inflammatory response in a murine model of Crohn disease. The Journal of biological chemistry 130 15691843
2015 A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production. Nature communications 115 25778803
2012 Yersinia pseudotuberculosis effector YopJ subverts the Nod2/RICK/TAK1 pathway and activates caspase-1 to induce intestinal barrier dysfunction. Cell host & microbe 109 22520462
2007 The NOD2-RICK complex signals from the plasma membrane. The Journal of biological chemistry 98 17355968
2022 Fusobacterium nucleatum promotes esophageal squamous cell carcinoma progression via the NOD1/RIPK2/NF-κB pathway. Cancer letters 97 35033591
2015 Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors. Chemistry & biology 90 26320862
2014 In vivo inhibition of RIPK2 kinase alleviates inflammatory disease. The Journal of biological chemistry 88 25213858
2019 Fusobacterium nucleatum facilitates ulcerative colitis through activating IL-17F signaling to NF-κB via the upregulation of CARD3 expression. The Journal of pathology 84 31610014
2008 The TLR2-MyD88-NOD2-RIPK2 signalling axis regulates a balanced pro-inflammatory and IL-10-mediated anti-inflammatory cytokine response to Gram-positive cell walls. Cellular microbiology 82 18549453
2014 NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6. Mucosal immunology 72 24670424
2021 RIPK2 as a New Therapeutic Target in Inflammatory Bowel Diseases. Frontiers in pharmacology 65 33935757
2019 RICK/RIP2 is a NOD2-independent nodal point of gut inflammation. International immunology 64 31132297
2006 Solution structure of NOD1 CARD and mutational analysis of its interaction with the CARD of downstream kinase RICK. Journal of molecular biology 64 17054981
2003 CARD6 is a modulator of NF-kappa B activation by Nod1- and Cardiak-mediated pathways. The Journal of biological chemistry 61 12775719
2018 Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling. The EMBO journal 60 30026309
2014 Nod/Ripk2 signaling in dendritic cells activates IL-17A-secreting innate lymphoid cells and drives colitis in T-bet-/-.Rag2-/- (TRUC) mice. Proceedings of the National Academy of Sciences of the United States of America 60 24927559
2005 Inhibition of RIP2/RIck/CARDIAK activity by pyridinyl imidazole inhibitors of p38 MAPK. Molecular and cellular biochemistry 60 15724446
2021 Optimization of a Series of RIPK2 PROTACs. Journal of medicinal chemistry 54 34432979
2017 Human dendritic cells activated with MV130 induce Th1, Th17 and IL-10 responses via RIPK2 and MyD88 signalling pathways. European journal of immunology 53 28799230
2020 Postbiotics for NOD2 require nonhematopoietic RIPK2 to improve blood glucose and metabolic inflammation in mice. American journal of physiology. Endocrinology and metabolism 49 32101030
2021 Knockdown of RIPK2 Inhibits Proliferation and Migration, and Induces Apoptosis via the NF-κB Signaling Pathway in Gastric Cancer. Frontiers in genetics 47 33633788
2023 Fusobacterium nucleatum Extracellular Vesicles Promote Experimental Colitis by Modulating Autophagy via the miR-574-5p/CARD3 Axis. Inflammatory bowel diseases 45 35998069
2004 A role for rat inositol polyphosphate kinases rIPK2 and rIPK1 in inositol pentakisphosphate and inositol hexakisphosphate production in rat-1 cells. The Journal of biological chemistry 44 15528195
2020 Fusobacterium nucleatum Activates Endoplasmic Reticulum Stress to Promote Crohn's Disease Development via the Upregulation of CARD3 Expression. Frontiers in pharmacology 43 32153411
2020 RIPK2 NODs to XIAP and IBD. Seminars in cell & developmental biology 43 32631784
2013 LRRK2 and RIPK2 variants in the NOD 2-mediated signaling pathway are associated with susceptibility to Mycobacterium leprae in Indian populations. PloS one 41 24015287
2017 Identification of Potent and Selective RIPK2 Inhibitors for the Treatment of Inflammatory Diseases. ACS medicinal chemistry letters 40 29057049
2012 Joint NOD2/RIPK2 signaling regulates IL-17 axis and contributes to the development of experimental arthritis. Journal of immunology (Baltimore, Md. : 1950) 40 22491249
2022 Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis. Nature communications 39 35115556
2012 Pathogen-mediated proteolysis of the cell death regulator RIPK1 and the host defense modulator RIPK2 in human aortic endothelial cells. PLoS pathogens 35 22685397
2016 High Glucose and Lipopolysaccharide Activate NOD1- RICK-NF-κB Inflammatory Signaling in Mesangial Cells. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 33 27169686
2020 CARD3 Promotes Cerebral Ischemia-Reperfusion Injury Via Activation of TAK1. Journal of the American Heart Association 32 32349637
2017 Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia. Scientific reports 32 28484277
2015 HIV-1 protease cleaves the serine-threonine kinases RIPK1 and RIPK2. Retrovirology 31 26297639
2018 RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis. Cancers 30 29874851
2003 RICK activates a NF-kappaB-dependent anti-human cytomegalovirus response. The Journal of biological chemistry 30 14670961
2023 Receptor-interacting protein kinase 2 (RIPK2) profoundly contributes to post-stroke neuroinflammation and behavioral deficits with microglia as unique perpetrators. Journal of neuroinflammation 28 37777791
2019 XIAP controls RIPK2 signaling by preventing its deposition in speck-like structures. Life science alliance 26 31350258
2023 Recent advances in the development of RIPK2 modulators for the treatment of inflammatory diseases. Frontiers in pharmacology 25 36959850
2021 ATG16L1 negatively regulates RICK/RIP2-mediated innate immune responses. International immunology 25 32909611
2019 RIPK2-Mediated Autophagy and Negatively Regulated ROS-NLRP3 Inflammasome Signaling in GMCs Stimulated with High Glucose. Mediators of inflammation 25 31485193
2023 RIPK2: a promising target for cancer treatment. Frontiers in pharmacology 23 37324457
2022 NOD/RIPK2 signalling pathway contributes to osteoarthritis susceptibility. Annals of the rheumatic diseases 23 35732460
2020 NLRC3-like 1 inhibits NOD1-RIPK2 pathway via targeting RIPK2. Developmental and comparative immunology 23 32634524
2015 Expression and activity of NOD1 and NOD2/RIPK2 signalling in mononuclear cells from patients with rheumatoid arthritis. Scandinavian journal of rheumatology 23 26202066
2013 CARD3 deficiency exacerbates diet-induced obesity, hepatosteatosis, and insulin resistance in male mice. Endocrinology 22 23321697
2014 NOD2/RICK-dependent β-defensin 2 regulation is protective for nontypeable Haemophilus influenzae-induced middle ear infection. PloS one 21 24625812
2011 Cigarette smoke extract (CSE) delays NOD2 expression and affects NOD2/RIPK2 interactions in intestinal epithelial cells. PloS one 21 21931826
2020 RIPK2 Dictates Insulin Responses to Tyrosine Kinase Inhibitors in Obese Male Mice. Endocrinology 20 32473019
2015 NOD2 pathway via RIPK2 and TBK1 is involved in the aberrant catabolism induced by T-2 toxin in chondrocytes. Osteoarthritis and cartilage 20 25917637
2015 Regulatory role of CARD3 in left ventricular remodelling and dysfunction after myocardial infarction. Basic research in cardiology 20 26463597
2022 Discovery of Potent and Selective Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) Inhibitors for the Treatment of Inflammatory Bowel Diseases (IBDs). Journal of medicinal chemistry 19 35709396
2021 Activation of RIPK2-mediated NOD1 signaling promotes proliferation and invasion of ovarian cancer cells via NF-κB pathway. Histochemistry and cell biology 19 34825931
2018 A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis. Human molecular genetics 19 29659823
2009 RICK promotes inflammation and lethality after gram-negative bacterial infection in mice stimulated with lipopolysaccharide. Infection and immunity 19 19188356
2006 CARD tricks: controlling the interactions of CARD6 with RICK and microtubules. Cell cycle (Georgetown, Tex.) 19 16582588
2018 Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors. Bioorganic & medicinal chemistry letters 18 29409752
2023 Paired protein kinases PRKCI-RIPK2 promote pancreatic cancer growth and metastasis via enhancing NF-κB/JNK/ERK phosphorylation. Molecular medicine (Cambridge, Mass.) 17 37016317
2023 RIPK2 as a promising druggable target for autoimmune diseases. International immunopharmacology 16 37023697
2022 Card9 protects sepsis by regulating Ripk2-mediated activation of NLRP3 inflammasome in macrophages. Cell death & disease 16 35618701
2021 microRNA-210 and microRNA-3570 Negatively Regulate NF-κB-Mediated Inflammatory Responses by Targeting RIPK2 in Teleost Fish. Frontiers in immunology 16 33868233
2021 The potent and selective RIPK2 inhibitor BI 706039 improves intestinal inflammation in the TRUC mouse model of inflammatory bowel disease. American journal of physiology. Gastrointestinal and liver physiology 16 34494462
2020 Receptor-interacting protein kinase 2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling inhibitors based on a 3,5-diphenyl-2-aminopyridine scaffold. European journal of medicinal chemistry 16 32505849
2023 RIPK2 inhibitors for disease therapy: Current status and perspectives. European journal of medicinal chemistry 15 37531744
2023 Characterization of the Inflammatory Response Evoked by Bacterial Membrane Vesicles in Intestinal Cells Reveals an RIPK2-Dependent Activation by Enterotoxigenic Escherichia coli Vesicles. Microbiology spectrum 14 37306596
2012 The anti-inflammatory actions of IL-4 in human monocytes are not mediated by IL-10, RP105 or the kinase activity of RIPK2. Cytokine 14 22484241
2003 Equilibrium and kinetic folding of an alpha-helical Greek key protein domain: caspase recruitment domain (CARD) of RICK. Biochemistry 14 12755636
2024 N4BP3 facilitates NOD2-MAPK/NF-κB pathway in inflammatory bowel disease through mediating K63-linked RIPK2 ubiquitination. Cell death discovery 13 39420190
2021 Design of pyrido[2,3-d]pyrimidin-7-one inhibitors of receptor interacting protein kinase-2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling. European journal of medicinal chemistry 13 33601309
2020 A regulatory region on RIPK2 is required for XIAP binding and NOD signaling activity. EMBO reports 13 32954645
2015 Dysfunctional Crohn's Disease-Associated NOD2 Polymorphisms Cannot be Reliably Predicted on the Basis of RIPK2 Binding or Membrane Association. Frontiers in immunology 13 26500656
2013 RIP2/RICK-dependent cytokine production upon Yersinia enterocolitica infection in macrophages with TLR4 deficiency. Scandinavian journal of immunology 13 23952047
2023 Discovery of a novel RIPK2 inhibitor for the treatment of inflammatory bowel disease. Biochemical pharmacology 12 37315817
2013 Activation of NOD2/RIPK2 pathway induces mitochondrial injury to oligodendrocyte precursor cells in vitro and CNS demyelination in vivo. Journal of neuroimmunology 12 24169446
2023 RIPK2 promotes the progression of colon cancer by regulating BIRC3-mediated ubiquitination of IKBKG. Experimental cell research 11 37211186
2022 A pancancer analysis of the carcinogenic role of receptor-interacting serine/threonine protein kinase-2 (RIPK2) in human tumours. BMC medical genomics 9 35473583
2022 High expression of RIPK2 is associated with Taxol resistance in serous ovarian cancer. Journal of ovarian research 9 35477477
2015 CARD3 deficiency protects against colitis through reduced epithelial cell apoptosis. Inflammatory bowel diseases 9 25742400
2015 The expression of CCN2, IQSEC, RSPO1, DNAJC15, RIPK2, IL13RA2, IRS1, and IRS2 genes in blood of obese boys with insulin resistance. Fiziolohichnyi zhurnal (Kiev, Ukraine : 1994) 9 26040030
2012 The RIPK2 gene: a positional candidate for tick burden supported by genetic associations in cattle and immunological response of knockout mouse. Immunogenetics 9 22314416
2025 MYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2. Bone research 8 39746943
2025 Current advances on RIPK2 and its inhibitors in pathological processes: a comprehensive review. Frontiers in molecular neuroscience 8 40406369
2006 Substitutions of prolines examine their role in kinetic trap formation of the caspase recruitment domain (CARD) of RICK. Protein science : a publication of the Protein Society 8 16501221
2024 YOD1 sustains NOD2-mediated protective signaling in colitis by stabilizing RIPK2. EMBO reports 7 39333628
2023 A Look at Spinal Cord Injury in Canada: Rick Hansen Spinal Cord Injury Registry (RHSCIR) - 2021 SCI Data Summary. Topics in spinal cord injury rehabilitation 7 38174135
2021 RICK regulates the odontogenic differentiation of dental pulp stem cells through activation of TNF-α via the ERK and not through NF-κB signaling pathway. Cell biology international 7 33169892
2015 The immunomodulatory effects of barettin and involvement of the kinases CAMK1α and RIPK2. Immunopharmacology and immunotoxicology 7 26466644
2025 RIPK2 promotes colorectal cancer metastasis by protecting YAP degradation from ITCH-mediated ubiquitination. Cell death & disease 6 40185717
2024 Pharmacological inhibition of receptor-interacting protein kinase 2 (RIPK2) elicits neuroprotective effects following experimental ischemic stroke. Experimental neurology 6 38729551
2023 Design, synthesis and biological evaluation of 4-aminoquinoline derivatives as receptor-interacting protein kinase 2 (RIPK2) inhibitors. Journal of enzyme inhibition and medicinal chemistry 6 36408835

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