Affinage

RIPK4

Receptor-interacting serine/threonine-protein kinase 4 · UniProt P57078

Length
832 aa
Mass
91.6 kDa
Annotated
2026-06-10
80 papers in source corpus 33 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RIPK4 is a dimerization-dependent Ser/Thr kinase of the RIP kinase family that acts cell-autonomously within the keratinocyte lineage to drive epidermal differentiation and barrier formation (PMID:12446564, PMID:12194825, PMID:19626033). Its kinase domain crystallizes as a dimer resembling RIPK2 and BRAF, and engineered disruption of the dimer interface abolishes catalytic activity; Bartsocas-Papas disease mutations map to this domain and impair kinase function (PMID:29706531). Catalytically, RIPK4 phosphorylates the transcription factor IRF6 at Ser413/Ser424 to license its transactivation function, and the RIPK4–IRF6 axis co-regulates epidermal differentiation, cornification, lipid metabolism, and tight-junction gene programs required for a competent skin barrier (PMID:31578523, PMID:25784454, PMID:35220430). RIPK4 phosphorylates additional substrates that converge on epithelial adhesion and signaling: plakophilin-1 (PKP1) to support differentiation and desmosome integrity (PMID:28507225, PMID:35220430), Dishevelled-2 (DVL2) to activate canonical Wnt/β-catenin signaling (PMID:23371553), and LATS1/2 within liquid–liquid phase-separated condensates to engage non-canonical Hippo signaling and restrain YAP/TAZ in the epidermal granular layer (PMID:40570855). Loss of RIPK4 in mice produces perinatal lethality with abnormal epidermal differentiation, periderm defects, E-cadherin and claudin-1 mislocalization, and barrier failure (PMID:12194825, PMID:25430793, PMID:29317263). RIPK4 was originally defined as a PKCβ/δ-associated kinase that drives NF-κB and JNK activation through TRAF and IKKα/IKKβ engagement (PMID:12446564, PMID:11278382, PMID:10948194, PMID:12091384). RIPK4 protein levels are tightly set by ubiquitin-dependent turnover: trans-autophosphorylation creates a phosphodegron recognized by SCFβ-TrCP for K48-linked ubiquitination and degradation (PMID:29435596), while UCHL3-mediated deubiquitination at K469, promoted by GSK3β phosphorylation at Ser420, stabilizes the protein (PMID:38664501). Beyond skin, kinase-dependent phosphorylation of MFN2 promotes its degradation to support osteogenesis and myelopoiesis (PMID:40683865), and RIPK4 drives oxidative-stress and ferroptotic cell death by transcriptionally repressing ACSM1 (PMID:39316049). RIPK4 is itself a transcriptional target of NOTCH and functions as a tumor suppressor in squamous cell carcinoma through the NOTCH–RIPK4–IRF6–ELOVL4 axis (PMID:36765696). The timeline links RIPK4 kinase-dead and truncation mutations to Bartsocas-Papas syndrome (PMID:23371553, PMID:29706531, PMID:25784454).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 High

    Established RIPK4 as a catalytically active RIP-family Ser/Thr kinase coupling PKC signaling to NF-κB, defining its founding molecular identity and partners.

    Evidence Co-IP of PKCβ/δ and TRAFs, in vitro kinase assays, dominant-negative NF-κB/JNK reporters, and IKK epistasis in cells

    PMID:10948194 PMID:11278382 PMID:12091384 PMID:12446564

    Open questions at the time
    • Physiological substrates beyond autophosphorylation not yet defined
    • Whether NF-κB activation is direct or via adaptor recruitment unresolved
  2. 2002 High

    Defined the core in vivo role of RIPK4 as a cell-autonomous driver of epidermal differentiation acting in a pathway distinct from IKKα.

    Evidence RIP4 knockout mouse, skin grafting, and genetic epistasis with IKKα KO; later K14-transgene rescue

    PMID:12194825 PMID:19626033

    Open questions at the time
    • Direct kinase substrates mediating the differentiation defect not identified at this stage
    • Molecular basis of the IKKα-independent pathway unknown
  3. 2013 High

    Showed RIPK4 directly engages and phosphorylates Wnt pathway components, expanding its signaling output beyond NF-κB to canonical Wnt/β-catenin.

    Evidence Co-IP with DVL2/LRP6, kinase assays, β-catenin accumulation, and Xenopus epistasis with disease mutants

    PMID:23371553

    Open questions at the time
    • DVL2 phosphosites not mapped
    • Relationship between Wnt and epidermal differentiation functions unclear
  4. 2015 Medium

    Identified IRF6 as a key RIPK4 substrate, mechanistically linking kinase activity to a transcriptional differentiation program and to human disease alleles.

    Evidence Phosphosite mapping (Ser413/Ser424), reporter assays, proteasome inhibition, and VWS/BPS mutant analysis

    PMID:25784454

    Open questions at the time
    • Some methods inferred; single lab
    • Full target gene set of activated IRF6 not yet defined at this point
  5. 2017 High

    Broadened the RIPK4 substrate repertoire to the adhesion/cytoskeletal regulator PKP1 and tied substrate phosphorylation to carcinogenesis suppression.

    Evidence Quantitative phosphoproteomics, kinome screen, and Pkp1/Ripk4 KO mouse genetics

    PMID:28507225

    Open questions at the time
    • Functional consequence of specific PKP1 phosphosites not fully resolved
    • Mechanistic link between PKP1 phosphorylation and carcinogenesis incomplete
  6. 2018 High

    Resolved the structural and degradative logic of RIPK4 — dimerization-dependent activation and phosphodegron-driven SCFβ-TrCP turnover.

    Evidence X-ray crystallography with dimer-interface mutants; Co-IP, K48-ubiquitination assays, and phosphodegron mutagenesis

    PMID:29435596 PMID:29706531

    Open questions at the time
    • Trigger for physiological dimerization in vivo not defined
    • How autophosphorylation timing couples activation to degradation unresolved
  7. 2018 Medium

    Documented context-dependent oncogenic signaling outputs of RIPK4 in cancer cells, contrasting with its tumor-suppressive role in skin.

    Evidence Knockdown/overexpression with K63-ubiquitination, NF-κB localization, PEBP1/RAF1-ERK, STAT3, and IKK assays across tumor models

    PMID:29436617 PMID:29867225 PMID:30044012 PMID:30212707

    Open questions at the time
    • Direct vs indirect mechanisms for ubiquitin and STAT3 effects not separated
    • Some single Co-IP claims lack reciprocal validation
  8. 2019 High

    Provided definitive in vivo proof that RIPK4 kinase activity drives epidermal barrier formation through IRF6-controlled differentiation and lipid/tight-junction programs.

    Evidence Kinase-dead knock-in mouse with RNA-seq, ChIP-seq, ATAC-seq, and Irf6 KO comparison

    PMID:31578523

    Open questions at the time
    • Contribution of non-IRF6 substrates to the barrier phenotype not quantified
    • How RIPK4 is activated during normal differentiation unknown
  9. 2024 High

    Defined the stabilizing arm of RIPK4 regulation, balancing SCFβ-TrCP degradation via UCHL3-dependent deubiquitination gated by GSK3β phosphorylation.

    Evidence Site-specific mutagenesis (K469, Ser420), K48-ubiquitination assays, UCHL3 inhibitor, and Co-IP

    PMID:38664501

    Open questions at the time
    • Signals that toggle between degradation and stabilization in vivo unclear
    • Tissue-specific deployment of this switch not mapped
  10. 2024 High

    Revealed a death-promoting function of RIPK4 in oxidative stress and ferroptosis via transcriptional repression of ACSM1, with therapeutic implications for kidney injury.

    Evidence siRNA screen, kinase-dead mutant, proximal-tubule conditional KO, RNA-seq, and lipidomics

    PMID:39316049

    Open questions at the time
    • How RIPK4 represses ACSM1 transcriptionally not defined
    • Direct ferroptosis-relevant substrates not identified
  11. 2025 High

    Connected RIPK4 to non-canonical Hippo signaling and mitochondrial dynamics, identifying LATS1/2 (via condensates) and MFN2 as new substrates governing skin barrier, bone, and hematopoiesis.

    Evidence Kinome screens, in vitro kinase assays, condensate live-imaging, Ripk4 and Yap/Taz KO mice, MFN2 Co-IP and degradation assays

    PMID:40570855 PMID:40683865

    Open questions at the time
    • LATS1/2 and MFN2 phosphosites and their interplay with other substrates not fully integrated
    • Determinants of RIPK4 phase separation in vivo unclear
  12. 2025 Medium

    Extended RIPK4's pro-apoptotic role to a p53 interaction enhancing Ser15 phosphorylation under genotoxic stress.

    Evidence Genome-wide CRISPR screen, Co-IP with deletion mapping (1–490 aa), and apoptosis readouts in RIPK4 KO cells

    PMID:41061783

    Open questions at the time
    • Whether RIPK4 directly phosphorylates p53 not established
    • Single lab, no reciprocal structural validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single kinase is partitioned between opposing roles — tumor suppression and differentiation in skin versus pro-death and oncogenic signaling in other tissues — and what upstream cue activates it in each context remains unresolved.
  • No unifying model reconciles tissue-specific substrate selection
  • Physiological activating ligand/stimulus for RIPK4 dimerization not identified
  • Substrate prioritization among IRF6, PKP1, DVL2, LATS1/2, and MFN2 not quantitatively defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 4 GO:0140110 transcription regulator activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3
Partners
BTRCDVL2IRF6LATS1MFN2PKCBPKP1UCHL3

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 RIPK4 (RIP4/DIK/PKK) was identified as a novel RIP kinase family member containing an N-terminal Ser/Thr kinase domain and C-terminal ankyrin repeats. Overexpression activates NF-κB and JNK; kinase-inactive RIPK4 or the ankyrin-repeat fragment act as dominant negatives on NF-κB induction. RIPK4 binds TRAF1, TRAF3, and TRAF6, and dominant-negative versions of these TRAFs inhibit RIPK4-induced NF-κB activation. RIPK4 is cleaved after Asp340 and Asp378 during Fas-induced apoptosis. Overexpression, dominant-negative constructs, co-immunoprecipitation (TRAF binding), NF-κB/JNK reporter assays, Fas-induced apoptosis cleavage mapping EMBO reports High 12446564
2001 RIPK4 (PKK/DIK) physically associates with protein kinase Cβ (PKCβ) and PKCδ. PKK exhibits intrinsic protein kinase activity in vitro (autophosphorylation and substrate phosphorylation). PKK exists in three phosphorylation states correlating with membrane association. Conversion from the underphosphorylated 100-kDa form to the phosphorylated 110-kDa form requires an active catalytic domain. PKK does not phosphorylate PKCβ, but PKCβ may phosphorylate PKK. Co-immunoprecipitation, in vitro kinase assay, subcellular fractionation, mutagenesis of catalytic domain The Journal of biological chemistry High 10948194 11278382
2002 RIPK4 (PKK) mediates PKC-activated NF-κB signaling independently of Bcl10 and IKKγ (NEMO), but requires IKKα and IKKβ. A catalytically inactive PKK mutant blocked NF-κB activation by phorbol ester and Ca2+-ionophore but not by TNF-α or IL-1β. Co-expression of PKCβI reversed the dominant-negative effect of catalytic-inactive PKK, confirming functional association with PKCβ. Dominant-negative and kinase-dead mutants, NF-κB reporter assays, epistasis with IKK subunit mutants and Bcl10/Bimp1 The Journal of biological chemistry High 12091384
2002 RIP4 deficiency in mice causes perinatal lethality with abnormal epidermal differentiation. Despite phenotypic similarities to IKKα-deficient mice, RIP4 and IKKα function in distinct pathways. RIP4 functions cell-autonomously within the keratinocyte lineage; RIP4-deficient skin grafted onto a normal host fails to fully differentiate. RIP4 knockout mouse model, skin grafting, genetic epistasis with IKKα KO Current biology : CB High 12194825
2013 RIPK4 directly interacts with DVL2 (Dishevelled-2) constitutively and with LRP6 after Wnt3a stimulation. RIPK4 phosphorylates DVL2, promoting canonical Wnt/β-catenin signaling and accumulation of cytosolic β-catenin. Catalytically inactive RIPK4 and Bartsocas-Papas disease mutants fail to activate Wnt signaling. In Xenopus embryos, Ripk4 synergizes with Xwnt8 and morpholino-mediated knockdown antagonizes Wnt signaling. Co-immunoprecipitation, kinase assays, overexpression/knockdown in Xenopus embryos, β-catenin accumulation assay, transcriptional reporter Science (New York, N.Y.) High 23371553
2019 RIPK4 kinase activity is required for mouse epidermal development in vivo. RIPK4 phosphorylates IRF6 at Ser413 and Ser424, priming IRF6 for transcriptional activation. RIPK4 and IRF6 co-regulate the same epidermal differentiation programs including lipid metabolism and tight junction genes; IRF6 deficiency causes abnormal stratum corneum lipid composition and defective epidermal barrier function. Kinase-dead knock-in mouse, RNA-seq, ChIP-seq, ATAC-seq, Irf6 KO mouse, phosphorylation site mapping Nature High 31578523
2017 RIPK4 phosphorylates PKP1 (plakophilin-1) at its N-terminal domain. Phosphorylation of PKP1 by RIPK4 is essential for epidermal differentiation; loss of function of either Pkp1 or Ripk4 impairs skin differentiation and enhances epidermal carcinogenesis in vivo. Quantitative phosphoproteomics, kinome cDNA library screen, genome-editing (Pkp1/Ripk4 KO), mouse genetics The EMBO journal High 28507225
2014 RIPK4 deficiency in mice causes epithelial fusions associated with abnormal periderm development and aberrant E-cadherin localization on the apical membrane of outer peridermal cells. In Xenopus, RIPK4 depletion phenocopies dominant-negative IRF6, causes absence of ectodermal epiboly and loss of cortical actin in ectodermal cells. IRF6 controls RIPK4 expression, and wild-type but not kinase-dead RIPK4 rescues the IRF6-loss gastrulation defect. RIPK4 is required for cortical actin organization in mouse epidermis and HaCaT cells. Ripk4 KO mouse, Xenopus morpholino knockdown, dominant-negative IRF6, kinase-dead rescue experiments, immunofluorescence for E-cadherin and actin Cell death and differentiation High 25430793
2018 Crystal structure of murine Ripk4 kinase domain was solved in ATP- and inhibitor-bound forms. The crystallographic dimer resembles those of RIPK2 and BRAF. Engineered mutations demonstrate that the dimeric entity is required for Ripk4 catalytic activity. Bartsocas-Papas disease mutations impair protein structure and/or kinase activity. X-ray crystallography, engineered dimer-interface mutations, cell-based kinase activity assays Structure (London, England : 1993) High 29706531
2018 SCFβ-TrCP ubiquitin E3 ligase complex binds a conserved phosphodegron motif in the intermediate domain of RIPK4, leading to K48-linked ubiquitination and proteasomal degradation. Recruitment of β-TrCP depends on RIPK4 activation and trans-autophosphorylation. β-TrCP knockdown causes RIPK4-dependent actin stress fiber formation, cell scattering, and increased motility in keratinocytes. Co-immunoprecipitation, ubiquitination assays, phosphodegron mutagenesis, β-TrCP knockdown, actin cytoskeleton imaging Cellular and molecular life sciences : CMLS High 29435596
2010 Epidermal-specific (K14-driven) RIP4 transgene rescues the epidermal phenotype of RIP4−/− mice, confirming cell-autonomous function in the epidermis. The K14-RIP4 transgene fails to rescue epidermal differentiation in IKKα−/− or Sfn(Er/Er) mice, placing RIP4 in a PKC-specific signaling pathway distinct from IKKα. TPA-induced neutrophilic inflammation in K14-RIP4 mice is TNFR1-independent. Transgenic rescue in RIP4 KO and IKKα KO backgrounds, TPA treatment, TNFR1 KO epistasis The Journal of investigative dermatology High 19626033
2015 RIPK4 phosphorylates IRF6 at Ser413 and Ser424 in the C-terminal domain, inducing IRF6 transactivator function. The VWS-associated IRF6 p.Arg412X truncation undergoes rapid proteasome-dependent degradation and cannot be activated by RIPK4. The BPS-associated RIPK4 p.Ser376X mutation impairs IRF6 transactivation and also inhibits RIPK4-induced β-catenin stabilization. Phosphorylation site mapping, reporter gene assays, proteasome inhibitor experiments, IRF6/RIPK4 mutant expression Cellular signalling Medium 25784454
2016 RIPK4 induces expression of proinflammatory chemokines CCL5 and CXCL11 in oral keratinocytes via IRF6. RIPK4 overexpression strongly induced CCL5 and CXCL11, but not IL-8 or TNF. Gene silencing showed both RIPK4 and IRF6 are required for inducible expression. Gene reporter assays indicated RIPK4 stimulates IRF6 transactivation of CCL5 and CXCL11 promoters. RIPK4 overexpression, siRNA knockdown, gene reporter assays, PKC pathway activation Cytokine Medium 27014863
2016 RIPK4 is required for PKC-induced upregulation of ELF3 in keratinocytes, acting through an IRF6-GRHL3-ELF3 transcription factor hierarchy. RIPK4 and IRF6 also regulate expression of cornification genes SPRR1A, SPRR1B, and transglutaminase TGM1. RIPK4 upregulates TGM2 independently of IRF6. PMA stimulation, RIPK4 and IRF6 siRNA knockdown, qPCR for target genes Cellular signalling Medium 27667567
2018 RIPK4 promotes K63-linked polyubiquitination of TRAF2, RIP1, and NEMO, leading to sustained NF-κB-p65 nuclear localization and VEGF-A upregulation in bladder cancer cells. RIPK4 knockdown/overexpression, ubiquitination assays (K63-linkage), NF-κB nuclear localization by immunofluorescence, in vitro and in vivo functional assays British journal of cancer Medium 29867225
2018 RIPK4 promotes cell migration and invasion via proteasome-mediated degradation of PEBP1 (phosphatidylethanolamine binding protein 1), which relieves PEBP1-mediated suppression of the RAF1/MEK/ERK pathway. Suppression of PEBP1 degradation abolished RIPK4-induced RAF1/MEK/ERK activation. RIPK4 overexpression/knockdown, PEBP1 degradation assays (proteasome inhibitor), RAF1/MEK/ERK pathway readouts, migration/invasion assays International journal of oncology Medium 29436617
2017 RIP4 loss in lung adenocarcinoma enhances STAT3 signaling; RIPK4 overexpression inhibits STAT3 activation, which abrogates IL-6-dependent induction of lysyl oxidase (a collagen cross-linking enzyme). Co-expression of constitutively active STAT3 restores invasive/tumorigenic potential in Rip4-overexpressing cells. RIPK4 knockdown/overexpression, autochthonous mouse lung AC model, STAT3 pathway readouts, IL-6 treatment, STAT3 co-expression rescue Cell death and differentiation Medium 28574510
2018 RIPK4 interacts with STAT3 in keratinocytes (co-immunoprecipitation). This interaction enhances STAT3 phosphorylation, and RIPK4-activated STAT3 transcriptionally regulates IL-17-mediated CCL20 expression in HaCaT cells. Co-immunoprecipitation, microarray, RIPK4 overexpression, STAT3 reporter assay Experimental dermatology Medium 30044012
2018 RIPK4 enhances the interaction between IKKα and IKKβ, activating NF-κB signaling to promote VEGF expression in nasopharyngeal carcinoma cells. Co-immunoprecipitation, RIPK4 knockdown/overexpression, NF-κB pathway assays Biomedicine & pharmacotherapy Low 30212707
2018 A20 (ubiquitin-editing enzyme) interacts with RIPK4 and modifies ubiquitin chains on RIPK4 to regulate Wnt/β-catenin signaling. Loss of A20 causes dysregulation of Wnt-dependent gene expression, and this occurs through RIPK4. A20 KO cell lines (genome editing), RNAseq, co-immunoprecipitation, ubiquitination assays PloS one Medium 29718933
2019 RIPK4 suppresses canonical Smad-mediated TGF-β1 signaling in keratinocytes. RIPK4 inhibits TGF-β1-induced Smad2/3 phosphorylation, Smad2/3-Smad4 interaction, nuclear localization of Smad2/3, and TGF-β1-induced gene expression. This suppressive effect requires RIPK4 kinase activity. RIPK4 also suppresses TGF-β1-mediated cell migration. RIPK4 overexpression and kinase-dead mutant in HaCaT cells, Smad phosphorylation assays, nuclear fractionation, wound-scratch assay Cell biology international Medium 31825120
2022 RIPK4 regulates PVRL4/nectin-4 expression in keratinocytes transcriptionally via IRF6 (a RIPK4 phosphorylation target). Defective RIPK4 kinase activity causes loss of PVRL4/nectin-4 expression in patient epidermis and primary keratinocytes. RIPK4 also modulates desmosome morphology through plakophilin-1 and desmoplakin, implicating RIPK4 in a p63-IRF6 loop controlling cell adhesion. Patient-derived primary keratinocytes with RIPK4 mutations, IRF6 transcriptional reporter, desmosome ultrastructure (EM), immunofluorescence Human molecular genetics Medium 35220430
2018 Keratinocyte-specific RIPK4 KO (RIPK4EKO) mice show loss of claudin-1 membrane localization causing tight junction leakiness and excessive water loss leading to neonatal death. RIPK4 full KO-associated epithelial fusions are E-cadherin dependent, as keratinocyte-specific E-cadherin deletion rescues fusion phenotypes in RIPK4 full KO mice. Conditional KO mouse (Cre-lox), tight junction/claudin immunostaining, E-cadherin conditional double KO The Journal of investigative dermatology High 29317263
2006 siRNA-mediated suppression of RIP4 in keratinocytes reduces NF-κB activation and enhances expression of epidermal differentiation markers. RIP4 expression is downregulated in hyperproliferative keratinocytes at wound edges and returns to basal levels after wound repair completion. siRNA knockdown, NF-κB reporter assay, differentiation marker expression, wound-model in vivo The Journal of investigative dermatology Medium 17039240
2024 Upon ROS induction, RIPK4 is rapidly activated and its kinase activity is required for cell death by oxidative stress and ferroptosis. RIPK4 transcriptionally represses ACSM1; loss of ACSM1 augments ferroptotic death through increased ACSL4 and decreased monounsaturated fatty acid/PUFA balance. RIPK4-specific ablation in kidney proximal tubules protects mice from cisplatin- and ischemia/reperfusion-induced acute kidney injury. siRNA screen, kinase-dead mutant, conditional KO (kidney proximal tubule), RNA-seq, lipidomics, ACSM1 knockdown rescue Proceedings of the National Academy of Sciences of the United States of America High 39316049
2024 ROCK1 inhibits AMPK Thr172 phosphorylation by binding to RIPK4. ROCK1 inhibition with fasudil improves diabetic wound healing partly through the ROCK1/RIPK4/AMPK pathway, enhancing eNOS activity and reducing mitochondrial ROS in endothelial cells. Bioinformatics + co-immunoprecipitation (ROCK1-RIPK4 interaction), ROCK1 inhibitor (fasudil), ROCK1 siRNA, AMPK phosphorylation assays, diabetic mouse wound model Acta pharmacologica Sinica Medium 38538716
2025 RIPK4 functions as an alternative upstream kinase for LATS1/2 in the Hippo pathway. RIPK4 directly phosphorylates LATS1/2 after recruiting them into liquid-liquid phase separation condensates. Ripk4 KO in mice activates Yap/Taz in the epidermal granular layer, repressing cholesterol biosynthesis. Ablation of Yap/Taz partially rescues the skin barrier defect of Ripk4 KO mice. Disease-derived RIPK4 mutants show defects in LATS1/2 activation due to impaired kinase activity or disrupted phase separation. Kinome library screen, Ripk4 KO mice, Yap/Taz conditional KO rescue, in vitro kinase assays, live-cell imaging of condensate formation, disease mutant analysis Developmental cell High 40570855
2025 RIPK4 interacts with MFN2 (mitofusin-2) in a kinase-dependent manner and phosphorylates MFN2, promoting its proteasomal degradation. This disrupts mitochondrial fission/fusion balance to promote osteogenesis. Osteoblast-lineage RIPK4 also maintains bone marrow myelopoiesis through MFN2-mediated mitochondrial transfer. RIPK4 global KO mouse, co-immunoprecipitation, phosphorylation assay, proteasome inhibitor rescue, mitochondrial transfer assay, bone/hematopoiesis phenotyping Nature communications High 40683865
2024 UCHL3 deubiquitinates RIPK4 at K469 by removing K48-linked ubiquitin chains, stabilizing RIPK4 protein. GSK3β phosphorylates RIPK4 at Ser420, enhancing its interaction with UCHL3 and further promoting deubiquitination and stabilization. Co-immunoprecipitation, ubiquitination assays (K48-specific), UCHL3 inhibitor (TCID), site-directed mutagenesis (K469, Ser420), single-cell sequencing Oncogene High 38664501
2022 LINC01537 (lncRNA) stabilizes RIPK4 protein by reducing its interaction with TRIM25 ubiquitin ligase and thereby reducing K48-linked ubiquitination-dependent degradation of RIPK4, leading to enhanced NF-κB signaling. RNA pull-down, RNA immunoprecipitation, ubiquitination assays, RIPK4 interaction with TRIM25 Cancers Medium 36358656
2023 RIPK4 is a direct transcriptional target of NOTCH signaling. Tumor suppressive function of RIPK4 in squamous cell carcinoma requires its kinase activity (kinase-dead Ripk4 fails to suppress SCC in vivo). ELOVL4 is identified as a critical downstream target of the NOTCH-RIPK4-IRF6 axis; Elovl4 loss triggers SCC development, and Elovl4 overexpression suppresses Ripk4-deficient tumor growth. Autochthonous mouse SCC models (Pik3caH1047R), kinase-dead Ripk4 rescue, CRISPR screen for downstream mediators, transcriptional profiling Cancers High 36765696
2025 RIPK4 directly interacts with p53 via its N-terminal 1-490 aa region and enhances p53 Ser15 phosphorylation and pro-apoptotic activity in the context of AFB1-induced cytotoxicity. RIPK4 KO reduces apoptosis markers (APAF1, Cyt-c, cleaved caspase-9/-3) and increases Bcl-2. CRISPR/Cas9 genome-wide screen, co-immunoprecipitation (RIPK4 deletion constructs), flow cytometry for apoptosis, Western blot for p53 Ser15 phosphorylation International journal of biological macromolecules Medium 41061783

Source papers

Stage 0 corpus · 80 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 RIP4 (DIK/PKK), a novel member of the RIP kinase family, activates NF-kappa B and is processed during apoptosis. EMBO reports 116 12446564
2013 Phosphorylation of Dishevelled by protein kinase RIPK4 regulates Wnt signaling. Science (New York, N.Y.) 89 23371553
2002 RIP4 is an ankyrin repeat-containing kinase essential for keratinocyte differentiation. Current biology : CB 89 12194825
2011 Mutations in RIPK4 cause the autosomal-recessive form of popliteal pterygium syndrome. American journal of human genetics 76 22197489
2019 The RIPK4-IRF6 signalling axis safeguards epidermal differentiation and barrier function. Nature 75 31578523
2011 Exome sequence identifies RIPK4 as the Bartsocas-Papas syndrome locus. American journal of human genetics 74 22197488
2001 Protein kinase C-associated kinase (PKK), a novel membrane-associated, ankyrin repeat-containing protein kinase. The Journal of biological chemistry 54 11278382
2000 DIK, a novel protein kinase that interacts with protein kinase Cdelta. Cloning, characterization, and gene analysis. The Journal of biological chemistry 52 10948194
2017 Phosphorylation of Pkp1 by RIPK4 regulates epidermal differentiation and skin tumorigenesis. The EMBO journal 51 28507225
2018 RIPK4 promotes bladder urothelial carcinoma cell aggressiveness by upregulating VEGF-A through the NF-κB pathway. British journal of cancer 49 29867225
2018 RIPK4/PEBP1 axis promotes pancreatic cancer cell migration and invasion by activating RAF1/MEK/ERK signaling. International journal of oncology 48 29436617
2019 Delivery of RIPK4 small interfering RNA for bladder cancer therapy using natural halloysite nanotubes. Science advances 47 31579820
2006 Regulation of NF-kappaB activity and keratinocyte differentiation by the RIP4 protein: implications for cutaneous wound repair. The Journal of investigative dermatology 47 17039240
2010 RIP4 regulates epidermal differentiation and cutaneous inflammation. The Journal of investigative dermatology 46 19626033
2014 A novel RIPK4-IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes. Cell death and differentiation 42 25430793
2021 MicroRNA miR-330-3p suppresses the progression of ovarian cancer by targeting RIPK4. Bioengineered 40 33487072
2002 Protein kinase C-associated kinase (PKK) mediates Bcl10-independent NF-kappa B activation induced by phorbol ester. The Journal of biological chemistry 37 12091384
2020 Insight Into the Function of RIPK4 in Keratinocyte Differentiation and Carcinogenesis. Frontiers in oncology 32 32923402
2019 IONIS-PKKRx a Novel Antisense Inhibitor of Prekallikrein and Bradykinin Production. Nucleic acid therapeutics 28 30817230
2017 RIP4 inhibits STAT3 signaling to sustain lung adenocarcinoma differentiation. Cell death and differentiation 28 28574510
2009 RIP4 is a target of multiple signal transduction pathways in keratinocytes: implications for epidermal differentiation and cutaneous wound repair. Experimental cell research 28 19818768
1985 Naturally occurring BK virus variants (JL and Dik) with deletions in the putative early enhancer-promoter sequences. Journal of virology 28 2981352
2014 Retroviral insertional mutagenesis in telomerase-immortalized hepatocytes identifies RIPK4 as novel tumor suppressor in human hepatocarcinogenesis. Oncogene 27 24413083
2014 RIPK4 is downregulated in poorly differentiated tongue cancer and is associated with migration/invasion and cisplatin-induced apoptosis. The International journal of biological markers 26 24519546
1997 Genetic and behavioural evidence of monogamy in a mammal, Kirk's dik-dik (Madoqua kirkii). Proceedings. Biological sciences 26 9178540
2018 RIPK4 promoted the tumorigenicity of nasopharyngeal carcinoma cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 23 30212707
2024 RIPK4 promotes oxidative stress and ferroptotic death through the downregulation of ACSM1. Proceedings of the National Academy of Sciences of the United States of America 21 39316049
2020 Silencing of RIPK4 inhibits epithelial‑mesenchymal transition by inactivating the Wnt/β‑catenin signaling pathway in osteosarcoma. Molecular medicine reports 21 32016450
2016 RIPK4 activates an IRF6-mediated proinflammatory cytokine response in keratinocytes. Cytokine 20 27014863
2018 RIP4 upregulates CCL20 expression through STAT3 signalling in cultured keratinocytes. Experimental dermatology 19 30044012
2018 Keratinocyte-Specific Ablation of RIPK4 Allows Epidermal Cornification but Impairs Skin Barrier Formation. The Journal of investigative dermatology 17 29317263
2018 RIPK4 activity in keratinocytes is controlled by the SCFβ-TrCP ubiquitin ligase to maintain cortical actin organization. Cellular and molecular life sciences : CMLS 17 29435596
2015 Disease-associated mutations in IRF6 and RIPK4 dysregulate their signalling functions. Cellular signalling 17 25784454
1995 Different rates of mitochondrial DNA sequence evolution in Kirk's dik-dik (Madoqua kirkii) populations. Molecular phylogenetics and evolution 17 8845965
2023 The NOTCH-RIPK4-IRF6-ELOVL4 Axis Suppresses Squamous Cell Carcinoma. Cancers 16 36765696
2018 Crystal Structure of Ripk4 Reveals Dimerization-Dependent Kinase Activity. Structure (London, England : 1993) 16 29706531
2016 A novel regulatory relationship between RIPK4 and ELF3 in keratinocytes. Cellular signalling 16 27667567
2014 PKK suppresses tumor growth and is decreased in squamous cell carcinoma of the skin. The Journal of investigative dermatology 16 25285922
2023 Vemurafenib and Dabrafenib Downregulates RIPK4 Level. Cancers 15 36765875
2023 m6A-modified RIPK4 facilitates proliferation and cisplatin resistance in epithelial ovarian cancer. Gynecologic oncology 15 38086167
2010 Cytotypes of Kirk's dik-dik (Madoqua kirkii,Bovidae) show multiple tandem fusions. Cytogenetic and genome research 15 21124018
2021 Downregulation of RIPK4 Expression Inhibits Epithelial-Mesenchymal Transition in Ovarian Cancer through IL-6. Journal of immunology research 14 33855091
2021 RIPK4 Suppresses the Invasion and Metastasis of Hepatocellular Carcinoma by Inhibiting the Phosphorylation of STAT3. Frontiers in molecular biosciences 13 34222329
2018 A20 regulates canonical wnt-signaling through an interaction with RIPK4. PloS one 13 29718933
2024 ROCK1 inhibition improves wound healing in diabetes via RIPK4/AMPK pathway. Acta pharmacologica Sinica 12 38538716
2023 RIPK4 downregulation impairs Wnt3A-stimulated invasiveness via Wnt/β-catenin signaling in melanoma cells and tumor growth in vivo. Cellular signalling 12 37871667
2017 Influence of protein kinase RIPK4 expression on the apoptosis and proliferation of chondrocytes in osteoarthritis. Molecular medicine reports 12 29257245
2022 LncRNA LINC01537 Promotes Gastric Cancer Metastasis and Tumorigenesis by Stabilizing RIPK4 to Activate NF-κB Signaling. Cancers 11 36358656
2015 Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas-Papas and CHAND syndromes. American journal of medical genetics. Part A 11 26129644
2018 PKK deletion in basal keratinocytes promotes tumorigenesis after chemical carcinogenesis. Carcinogenesis 9 29186361
2022 RIPK4 regulates cell-cell adhesion in epidermal development and homeostasis. Human molecular genetics 8 35220430
2021 Deciphering the Functional Role of RIPK4 in Melanoma. International journal of molecular sciences 8 34768934
2019 RIPK4 suppresses the TGF-β1 signaling pathway in HaCaT cells. Cell biology international 8 31825120
2024 The involvement of RIPK4 in TNF-α-stimulated IL-6 and IL-8 production by melanoma cells. Journal of cancer research and clinical oncology 7 38656555
2023 Directed Modification of a GHF11 Thermostable Xylanase AusM for Enhancing Inhibitory Resistance towards SyXIP-I and Application of AusMPKK in Bread Making. Foods (Basel, Switzerland) 7 37835228
2025 RIPK4 promotes epidermal differentiation through phase separation and activation of LATS1/2. Developmental cell 6 40570855
2024 miR-575/RIPK4 axis modulates cell cycle progression and proliferation by inactivating the Wnt/β-catenin signaling pathway through inhibiting RUNX1 in colon cancer. Molecular and cellular biochemistry 6 38480605
2016 A critical role for the protein kinase PKK in the maintenance of recirculating mature B cells and the development of B1 cells. Immunology letters 6 26921474
2025 Inhibition of the RIPK4 enhances suppression of human melanoma growth through vitamin D signaling. Molecular and cellular endocrinology 5 40490050
2025 RIPK4-mediated MFN2 degradation drives osteogenesis through mitochondrial fragmentation and restricts myelopoiesis by blocking mitochondrial transfer. Nature communications 5 40683865
2024 GSK3β and UCHL3 govern RIPK4 homeostasis via deubiquitination to enhance tumor metastasis in ovarian cancer. Oncogene 5 38664501
2017 Confirmation that RIPK4 mutations cause not only Bartsocas-Papas syndrome but also CHAND syndrome. American journal of medical genetics. Part A 5 28940926
2024 RIPK4 Downregulation Reduces ABCG2 Expression, Increasing BRAF-Mutated Melanoma Cell Susceptibility to Cisplatin- and Doxorubicin-Induced Apoptosis. Biomolecules 4 39766280
2022 Depletion of RIPK4 parallels higher malignancy potential in cutaneous squamous cell carcinoma. PeerJ 4 35186499
2022 RIPK4 Is an Immune Regulating-Associated Biomarker for Ovarian Cancer and Possesses Generalization Value in Pan-Cancer. Journal of immunology research 4 35310605
2017 PKK deficiency in B cells prevents lupus development in Sle lupus mice. Immunology letters 4 28274793
2021 A novel homozygous RIPK4 variant in a family with severe Bartsocas-Papas syndrome. American journal of medical genetics. Part A 3 33713555
2023 RIPK4 Promotes Cell Invasion and the Epithelial-Mesenchymal Transition in Ovarian Cancer. Frontiers in bioscience (Landmark edition) 2 38179758
2012 Preorbital carcinoma in two Kirk's dik-diks (Madoqua kirkii). Journal of comparative pathology 2 23063011
2026 RIPK4 function interferes with melanoma cell adhesion and metastasis. Molecular oncology 1 41660747
2025 Cancer-Associated Fibroblast-Derived RIPK4 Confers Cisplatin Resistance in Gastric Cancer by Activating the PI3K/AKT Pathway. Journal of biochemical and molecular toxicology 1 40522187
2022 [Corrigendum] Silencing of RIPK4 inhibits epithelial‑mesenchymal transition by inactivating the Wnt/β‑catenin signaling pathway in osteosarcoma. Molecular medicine reports 1 34981824
2000 Nitrogen metabolism and renal function in the dik-dik antelope (Rhynchotragus kirkii). Small ruminant research : the journal of the International Goat Association 1 10867322
2026 MicroRNA (miR)-489-3p contributes to lipopolysaccharide-induced HK-2 cell injury by targeting RIPK4 and inactivating the β-catenin signaling. Drug and chemical toxicology 0 41543014
2026 RIPK4 knockout enhances the antitumor effects of melatonin pretreatment in melanoma cells in vitro and in a xenograft model in zebrafish. Molecular and cellular endocrinology 0 42061551
2025 Identification of novel RIPK4 variants in a Chinese patient with Arthrogryposis Multiplex Congenita (AMC). Italian journal of pediatrics 0 39833848
2025 RIPK4-p53 interaction drives aflatoxin B1-induced renal mitochondrial apoptosis via Ser15 phosphorylation: A CRISPR-Cas9 mechanistic study. International journal of biological macromolecules 0 41061783
2025 [Corrigendum] RIPK4/PEBP1 axis promotes pancreatic cancer cell migration and invasion by activating RAF1/MEK/ERK signaling. International journal of oncology 0 41312735
2024 Lysophosphatidic acid down-regulates human RIPK4 mRNA in keratinocyte- derived cell lines. PloS one 0 38630705
2021 [The role of RIPK4 in epidermis physiology]. Postepy biochemii 0 34378900

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