{"gene":"PKP4","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1996,"finding":"p0071 (PKP4) was cloned and identified as a new armadillo family member with a central armadillo repeat region (10 repeats); it localizes at cell-cell borders and is expressed in the desmosomal plaque of some cultured epithelial cells, suggesting a role as an accessory component of adhesion plaques.","method":"cDNA cloning, antibody generation, immunolocalization","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — initial cloning and localization study; single lab but multiple methods (cloning, antibodies, immunofluorescence)","pmids":["8937994"],"is_preprint":false},{"year":1999,"finding":"The C-terminal fragment of presenilin 1 directly binds to p0071; nine out of ten armadillo repeats in p0071 are essential for mediating this interaction.","method":"Yeast two-hybrid system, domain deletion analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid with domain mapping; single lab, single method","pmids":["10092585"],"is_preprint":false},{"year":2000,"finding":"PAPIN (a multi-PDZ scaffolding protein) interacts with p0071 via its second PDZ domain; PAPIN and p0071 colocalize at cell-cell junctions in epithelial cells, suggesting PAPIN connects junction components to p0071.","method":"Yeast two-hybrid, co-localization immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus co-localization; single lab, two orthogonal methods","pmids":["10896674"],"is_preprint":false},{"year":2002,"finding":"The armadillo repeat domain of p0071 directly binds to VE-cadherin at the same region used by p120; overexpression of p0071 displaces p120 from intercellular junctions. The non-armadillo head domain of p0071 binds desmoplakin. p0071 is required to couple VE-cadherin to desmoplakin in cotransfection assays.","method":"Yeast two-hybrid deletion analysis, site-directed mutagenesis, transient expression co-localization, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — yeast two-hybrid domain mapping with mutagenesis, co-IP, and functional displacement assay; multiple orthogonal methods in single study","pmids":["12426320"],"is_preprint":false},{"year":2002,"finding":"ERBIN interacts with p0071 in vivo; the ERBIN PDZ domain binds the COOH-terminal PDZ-binding sequence of p0071. ERBIN colocalizes with p0071 at cell-cell contact regions in polarized MDCK cells.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus endogenous co-IP; single lab, two orthogonal methods","pmids":["12047349"],"is_preprint":false},{"year":2002,"finding":"p0071 localization at cell-cell contacts is independent of PAPIN and ERBIN; PAPIN, p0071, and ERBIN form a complex in 293T cells.","method":"Co-immunoprecipitation, calcium-switch assay, immunofluorescence","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus localization experiments; single lab, two orthogonal methods","pmids":["12370826"],"is_preprint":false},{"year":2003,"finding":"The head domain of p0071 is sufficient for desmosomal targeting and interacts with desmocollin 3a and desmoplakin; the armadillo repeat domain associates with non-desmosomal (classical) cadherins and enhances their membrane association; the tail domain localizes to the nucleus and associates with desmosomes; both head and armadillo repeat domains interact with plakoglobin at different binding sites.","method":"Yeast two-hybrid, membrane targeting (mom) assay, domain deletion constructs, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain dissection with multiple yeast two-hybrid and functional membrane targeting assays; multiple orthogonal methods, replicated across domains","pmids":["12615965"],"is_preprint":false},{"year":2006,"finding":"p0071 localizes to the midbody during cytokinesis and is essential for cell division; knockdown and overexpression of p0071 cause cytokinesis defects (multinucleated cells, apoptosis) through deregulation of RhoA activity. p0071 physically associates with RhoA and with the Rho-GEF Ect2; both p0071 and Ect2 are required together for full RhoA activation at the contractile ring.","method":"siRNA knockdown, overexpression, immunofluorescence midbody localization, co-immunoprecipitation with RhoA and Ect2, RhoA activity assays (G-LISA/pulldown)","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IPs, RhoA activity assays, KD/OE phenotype with defined cellular readout; multiple orthogonal methods in a high-quality study","pmids":["17115030"],"is_preprint":false},{"year":2007,"finding":"p0071 acts as a scaffold at the cleavage furrow to spatiotemporally regulate RhoA by interacting with both RhoA and the Rho-GEF Ect2; unlike p120ctn, p0071 is recruited to the cleavage furrow/midbody and controls local RhoA activation during cytokinesis.","method":"Review/commentary synthesizing co-IP, RhoA activity assay, and KD data from Wolf et al. 2006","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — synthesis of previously published co-IP and activity data; no new primary experiments presented","pmids":["17264675"],"is_preprint":false},{"year":2009,"finding":"p0071 targeting to the midbody during cytokinesis is mediated by the kinesin-II family member KIF3B; p0071 interacts with KIF3B, and KIF3B knockdown prevents p0071 midbody recruitment, reduces actin and phospho-myosin light chain at the midbody, and decreases active RhoA during cytokinesis. A p0071-MKLP1 motor domain fusion rescues RhoA activation in KIF3B-deficient cells.","method":"Co-immunoprecipitation, siRNA knockdown, rescue with fusion protein, immunofluorescence, RhoA activity assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, KD with defined phenotype, and domain fusion rescue experiment; multiple orthogonal methods","pmids":["19339549"],"is_preprint":false},{"year":2012,"finding":"Folliculin (FLCN) physically interacts with p0071; co-downregulation of FLCN or p0071 causes increased cell-cell adhesion and disruption of cell polarity in 3D lumen-forming assays. FLCN positively regulates RhoA and ROCK activity, consistent with p0071's known function.","method":"Yeast two-hybrid, co-immunoprecipitation, cell-based adhesion assays, 3D lumen assay, RhoA/ROCK activity measurement, in vivo mouse K14-Cre Bhd knockout","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus co-IP plus functional cell assays plus in vivo mouse model; multiple orthogonal methods","pmids":["23139756"],"is_preprint":false},{"year":2012,"finding":"Folliculin interacts with p0071 and colocalizes at cell junctions and at the midbody during cytokinesis; folliculin deficiency increases RhoA expression and activity, causes disordered cytokinesis, and leads to tight junction defects and E-cadherin mislocalization in renal tubular cells.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization, RhoA activity assay, ROCK inhibitor rescue, siRNA knockdown","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid, co-IP, RhoA activity assays, functional rescue with ROCK inhibitor; independently replicated FLCN-p0071 interaction (two labs)","pmids":["22965878"],"is_preprint":false},{"year":2013,"finding":"FMRP suppresses translation of the p0071 mRNA in a 3'-UTR-dependent manner; loss of FMRP leads to elevated p0071 protein levels, reorganized actin cytoskeleton (reduced stress fibers, lower F/G-actin ratio), and impaired neurite outgrowth; knockdown of p0071 in FMRP-deficient cells rescues the actin phenotype, while p0071 overexpression in FMRP-expressing cells mimics it.","method":"Fmr1 knockout MEFs, siRNA knockdown, overexpression, 3'-UTR reporter (translation assay), F/G-actin ratio measurement, immunofluorescence, neurite outgrowth assay","journal":"RNA","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (KO rescue), translational reporter, multiple cellular phenotypes; multiple orthogonal methods in single study","pmids":["24062571"],"is_preprint":false},{"year":2013,"finding":"p0071 interacts preferentially with active (GTP-bound) Rab11a; p0071 depletion causes perinuclear accumulation of Rab11, shifts transferrin receptor recycling from the slow Rab11-dependent to the fast Rab4-dependent pathway, and increases intercellular adhesion. Rab11a depletion increases p0071 recycling to cell contacts, identifying p0071 as a Rab11 cargo.","method":"Co-immunoprecipitation with GTP/GDP-loaded Rab11a, siRNA knockdown, transferrin receptor recycling assay, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — GTP-preference co-IP, functional recycling assay, bidirectional KD phenotypes; multiple orthogonal methods","pmids":["24163434"],"is_preprint":false},{"year":2017,"finding":"p0071 directly interacts with the KIF3 motor subunit KIF3B and with the kinesin cargo adaptor KAP3 (KIFAP3), acting as a stabilizing linker between KIF3B and KAP3; p0071 knockdown reduces secretion of chromogranin A and MMP9, impairs directional persistence of vesicle movement, and disrupts KIF3-dependent intracellular membrane vesicle transport.","method":"Co-immunoprecipitation, siRNA knockdown, vesicle tracking, secretion assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP identifying two binding partners, functional vesicle tracking, and secretion assays; multiple orthogonal methods","pmids":["28808088"],"is_preprint":false},{"year":2017,"finding":"p0071 interacts with E-cadherin in the cytoplasm of NSCLC cells; siRNA-mediated knockdown of p0071 inhibits invasion and migration ability of NSCLC cells and is associated with modulation of RhoA activity.","method":"Co-immunoprecipitation, siRNA knockdown, invasion/migration assay, RhoA activity assay","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — co-IP and siRNA knockdown with functional phenotype; single lab, limited mechanistic depth","pmids":["28898462"],"is_preprint":false},{"year":2020,"finding":"PKP4 was identified as a high-confidence proximity interactor of the Kir2.1 potassium channel; patch-clamp analysis validated that PKP4 modulates Kir2.1-controlled inward rectifier potassium currents.","method":"BioID proximity labeling, patch-clamp electrophysiology","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID interaction map plus functional patch-clamp validation; single lab, two orthogonal methods","pmids":["32541000"],"is_preprint":false},{"year":2023,"finding":"L. interrogans induces proteolysis of p0071 (and p120-catenin) at adherens junctions; p0071 proteolysis is prevented by the pan-caspase inhibitor Z-VAD-FMK, which also prevents displacement of both armadillo proteins from cell-cell junctions, indicating caspase-dependent degradation of p0071 contributes to E-cadherin destabilization and AJ disassembly.","method":"Proteomic analysis, immunofluorescence, chemical inhibitor studies (proteasomal, lysosomal, pan-caspase inhibitors)","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus chemical inhibition dissecting degradation pathway; single lab, two orthogonal approaches","pmids":["37795382"],"is_preprint":false},{"year":2025,"finding":"PKP4 (plakophilin 4) promotes formation of lateral spot adherens junctions (AJs) via an α-catenin-independent, cadherin–F-actin interaction mechanism, distinct from the canonical p120-driven AJ type that depends on α-catenin–actin interactions; this establishes that the two δ-catenins drive different cadherin clustering modes and AJ specialization.","method":"Overexpression and knockdown in epithelial cells, super-resolution/live imaging of cadherin clustering, actin perturbation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional imaging and genetic perturbation with defined phenotype; preprint, not yet peer-reviewed, single study","pmids":["bio_10.1101_2025.06.14.659701"],"is_preprint":true}],"current_model":"PKP4/p0071 is a multifunctional armadillo protein that (1) scaffolds adherens junctions and desmosomes by binding classical cadherins (via its armadillo repeats) and desmosomal proteins (via its head domain), promoting an α-catenin-independent lateral spot AJ type distinct from p120-driven junctions; (2) regulates cytokinesis by localizing to the midbody via KIF3B-dependent transport, where it physically associates with RhoA and the Rho-GEF Ect2 to activate RhoA locally at the contractile ring; (3) controls Rab11-dependent endosomal recycling as both a Rab11 regulator and cargo, linking junction dynamics to membrane trafficking; (4) acts as a stabilizing linker within the KIF3B–KAP3 transport complex to direct secretory vesicle movement; (5) is translationally repressed by FMRP, such that excess p0071 disrupts actin organization and neurite outgrowth; and (6) forms a complex with folliculin (FLCN) to negatively regulate cell-cell adhesion and RhoA signaling."},"narrative":{"mechanistic_narrative":"PKP4 (p0071) is a multifunctional armadillo-family protein that scaffolds intercellular junctions and couples them to actomyosin dynamics and membrane trafficking [PMID:8937994, PMID:12426320]. Through its central armadillo repeat domain it binds classical cadherins (VE-cadherin) at the same site used by p120, displacing p120 from junctions and enhancing cadherin membrane association, while its non-armadillo head domain engages desmosomal components (desmoplakin, desmocollin 3a) and plakoglobin, allowing PKP4 to physically couple classical cadherins to the desmosomal plaque [PMID:12426320, PMID:12615965]. Beyond static adhesion, PKP4 governs cytokinesis: it localizes to the cleavage furrow and midbody, where it scaffolds RhoA together with the Rho-GEF Ect2 to drive local RhoA activation at the contractile ring, and its loss or excess produces multinucleated cells and division failure [PMID:17115030]. Delivery of PKP4 to the midbody requires the kinesin-II motor KIF3B, and KIF3B-dependent transport is needed for actin, phospho-myosin, and active RhoA accumulation there [PMID:19339549]. More broadly, PKP4 acts as a stabilizing linker between KIF3B and the cargo adaptor KAP3 to support directional vesicle transport and secretion [PMID:28808088], and it both regulates and is carried by Rab11-dependent endosomal recycling, linking junction turnover to membrane recycling and tuning the level of intercellular adhesion [PMID:24163434]. PKP4 forms a complex with folliculin (FLCN) that negatively regulates cell-cell adhesion and supports RhoA/ROCK signaling [PMID:23139756, PMID:22965878], and its abundance is translationally repressed by FMRP, with excess PKP4 reorganizing the actin cytoskeleton and impairing neurite outgrowth [PMID:24062571].","teleology":[{"year":1996,"claim":"Established PKP4/p0071 as an armadillo-family protein resident at cell-cell borders and adhesion plaques, framing it as a candidate junctional component.","evidence":"cDNA cloning, antibody generation, and immunolocalization in cultured epithelial cells","pmids":["8937994"],"confidence":"Medium","gaps":["No binding partners identified","Functional role at junctions undefined"]},{"year":2000,"claim":"Identified scaffolding partners (PAPIN, presenilin 1, later ERBIN) that connect PKP4 to junctional and PDZ-protein networks, defining its interaction surfaces.","evidence":"Yeast two-hybrid with domain mapping and co-localization/co-IP in epithelial and 293T cells","pmids":["10092585","10896674","12047349","12370826"],"confidence":"Medium","gaps":["Functional consequence of each interaction at junctions not resolved","Several interactions rest on single-lab two-hybrid/Co-IP"]},{"year":2003,"claim":"Resolved PKP4 domain logic, showing the armadillo repeats bind classical cadherins (displacing p120) and the head domain binds desmosomal proteins, establishing PKP4 as a coupler of classical-cadherin and desmosomal adhesion systems.","evidence":"Yeast two-hybrid deletion analysis, mutagenesis, membrane-targeting assays, co-IP and displacement assays","pmids":["12426320","12615965"],"confidence":"High","gaps":["Cell-type specificity of cadherin vs desmosomal coupling not mapped","Structural basis of dual head/armadillo plakoglobin binding undefined"]},{"year":2006,"claim":"Revealed a non-adhesion role: PKP4 scaffolds RhoA and Ect2 at the midbody to drive local RhoA activation required for cytokinesis, explaining the multinucleation/apoptosis phenotype on perturbation.","evidence":"siRNA knockdown, overexpression, midbody immunofluorescence, reciprocal co-IP with RhoA and Ect2, RhoA activity assays","pmids":["17115030","17264675"],"confidence":"High","gaps":["How PKP4 spatially restricts RhoA activation mechanistically unclear","Relationship between junctional and cytokinetic pools not defined"]},{"year":2009,"claim":"Showed how PKP4 reaches the midbody — via KIF3B-mediated transport — linking motor-based delivery to RhoA activation and contractile-ring assembly.","evidence":"Co-IP, siRNA knockdown, motor-domain fusion rescue, immunofluorescence, RhoA activity assay","pmids":["19339549"],"confidence":"High","gaps":["Cargo recognition signal on PKP4 for KIF3B unknown","Whether transport carries RhoA/Ect2 with PKP4 not shown"]},{"year":2012,"claim":"Defined a PKP4-folliculin complex that negatively regulates cell-cell adhesion while supporting RhoA/ROCK signaling, independently replicated across two labs and an in vivo model.","evidence":"Yeast two-hybrid, co-IP, 3D lumen and adhesion assays, RhoA/ROCK activity, ROCK-inhibitor rescue, and K14-Cre Bhd knockout mice","pmids":["23139756","22965878"],"confidence":"High","gaps":["Direct biochemical mechanism by which FLCN-PKP4 tunes RhoA undefined","Disease relevance to FLCN-associated phenotypes not established in this corpus"]},{"year":2013,"claim":"Connected PKP4 to membrane trafficking and translational control: it is both a Rab11 regulator and Rab11 cargo governing recycling-pathway choice, and its abundance is repressed by FMRP with consequences for actin and neurite outgrowth.","evidence":"GTP/GDP-loaded Rab11a co-IP, transferrin recycling assays, Fmr1-KO MEFs, 3'-UTR reporter, F/G-actin and neurite assays with epistatic rescue","pmids":["24163434","24062571"],"confidence":"High","gaps":["How recycling status feeds back on junction assembly mechanistically unclear","FMRP-PKP4 axis tested in MEFs/cell models, not neurons in vivo"]},{"year":2017,"claim":"Generalized PKP4's transport role as a stabilizing KIF3B-KAP3 linker for secretory vesicle movement, and extended its RhoA-dependent adhesion function into cancer cell invasion.","evidence":"Co-IP, siRNA knockdown, vesicle tracking, secretion assays (chromogranin A, MMP9), and NSCLC invasion/migration with RhoA activity readout","pmids":["28808088","28898462"],"confidence":"High","gaps":["Cargo selectivity of PKP4-KIF3-KAP3 transport undefined","NSCLC mechanism is single-lab and correlative on RhoA"]},{"year":2020,"claim":"Expanded the PKP4 interactome to ion channel regulation, with PKP4 modulating Kir2.1 inward-rectifier potassium currents.","evidence":"BioID proximity labeling and patch-clamp electrophysiology","pmids":["32541000"],"confidence":"Medium","gaps":["Direct vs proximity interaction not distinguished","Physiological context of Kir2.1 modulation unknown"]},{"year":2023,"claim":"Showed PKP4 is a target of pathogen-driven junction disassembly, undergoing caspase-dependent proteolysis that contributes to E-cadherin destabilization.","evidence":"Proteomics, immunofluorescence, and pan-caspase/proteasomal/lysosomal inhibitor studies during L. interrogans infection","pmids":["37795382"],"confidence":"Medium","gaps":["Specific caspase and cleavage sites not identified","Whether PKP4 loss is cause or consequence of AJ disassembly not fully resolved"]},{"year":2025,"claim":"Distinguished PKP4 from p120 functionally, defining it as a driver of alpha-catenin-independent lateral spot adherens junctions via cadherin-F-actin coupling.","evidence":"Overexpression/knockdown, super-resolution and live imaging of cadherin clustering, and actin perturbation (preprint)","pmids":["bio_10.1101_2025.06.14.659701"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Molecular basis of the cadherin-F-actin link not defined"]},{"year":null,"claim":"How PKP4's distinct functional pools — junctional scaffolding, midbody RhoA control, Rab11 recycling, and KIF3-based transport — are coordinated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking PKP4 trafficking to junction turnover","No structural basis for its multivalent partner switching","In vivo physiological roles beyond cell models largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,6,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,9,13]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[12,18]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13,15]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,6,18]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7,9]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[13,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,10,11]}],"complexes":["PKP4-KIF3B-KAP3 transport complex","PKP4-RhoA-Ect2 midbody scaffold","PKP4-FLCN complex"],"partners":["RHOA","ECT2","KIF3B","KIFAP3","FLCN","RAB11A","DSP","JUP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99569","full_name":"Plakophilin-4","aliases":["p0071"],"length_aa":1192,"mass_kda":131.9,"function":"Plays a role as a regulator of Rho activity during cytokinesis. May play a role in junctional plaques","subcellular_location":"Cell junction, desmosome; Cytoplasm, cytoskeleton, spindle; Midbody; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q99569/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PKP4","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PKP4","total_profiled":1310},"omim":[{"mim_id":"613323","title":"FERM AND PDZ DOMAINS-CONTAINING PROTEIN 2; FRMPD2","url":"https://www.omim.org/entry/613323"},{"mim_id":"610697","title":"PDZ DOMAIN-CONTAINING 2; PDZD2","url":"https://www.omim.org/entry/610697"},{"mim_id":"604276","title":"PLAKOPHILIN 4; PKP4","url":"https://www.omim.org/entry/604276"},{"mim_id":"604275","title":"CATENIN, DELTA-2; CTNND2","url":"https://www.omim.org/entry/604275"},{"mim_id":"601214","title":"NAXOS DISEASE; NXD","url":"https://www.omim.org/entry/601214"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cell Junctions","reliability":"Enhanced"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":336.1}],"url":"https://www.proteinatlas.org/search/PKP4"},"hgnc":{"alias_symbol":["p0071"],"prev_symbol":[]},"alphafold":{"accession":"Q99569","domains":[{"cath_id":"1.25.10.10","chopping":"528-644","consensus_level":"medium","plddt":96.6975,"start":528,"end":644}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99569","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99569-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99569-F1-predicted_aligned_error_v6.png","plddt_mean":58.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PKP4","jax_strain_url":"https://www.jax.org/strain/search?query=PKP4"},"sequence":{"accession":"Q99569","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99569.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99569/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99569"}},"corpus_meta":[{"pmid":"8937994","id":"PMC_8937994","title":"Cloning and characterization of a new armadillo family member, p0071, associated with the junctional plaque: evidence for a subfamily of closely related proteins.","date":"1996","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/8937994","citation_count":124,"is_preprint":false},{"pmid":"12047349","id":"PMC_12047349","title":"ERBIN associates with p0071, an armadillo protein, at cell-cell junctions of epithelial cells.","date":"2002","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/12047349","citation_count":67,"is_preprint":false},{"pmid":"12615965","id":"PMC_12615965","title":"Targeting of p0071 to desmosomes and adherens junctions is mediated by different protein domains.","date":"2003","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/12615965","citation_count":64,"is_preprint":false},{"pmid":"17115030","id":"PMC_17115030","title":"The armadillo protein p0071 regulates Rho signalling during cytokinesis.","date":"2006","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17115030","citation_count":64,"is_preprint":false},{"pmid":"12827610","id":"PMC_12827610","title":"Immunohistochemical localization of plakophilins (PKP1, PKP2, PKP3, and p0071) in primary oropharyngeal tumors: correlation with clinical parameters.","date":"2003","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12827610","citation_count":62,"is_preprint":false},{"pmid":"23139756","id":"PMC_23139756","title":"Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23139756","citation_count":60,"is_preprint":false},{"pmid":"12426320","id":"PMC_12426320","title":"The Armadillo family protein p0071 is a VE-cadherin- and desmoplakin-binding protein.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12426320","citation_count":57,"is_preprint":false},{"pmid":"10896674","id":"PMC_10896674","title":"PAPIN. A novel multiple PSD-95/Dlg-A/ZO-1 protein interacting with neural plakophilin-related armadillo repeat protein/delta-catenin and p0071.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10896674","citation_count":57,"is_preprint":false},{"pmid":"10092585","id":"PMC_10092585","title":"Direct interaction of Alzheimer's disease-related presenilin 1 with armadillo protein p0071.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10092585","citation_count":57,"is_preprint":false},{"pmid":"12370826","id":"PMC_12370826","title":"Localization of p0071-interacting proteins, plakophilin-related armadillo-repeat protein-interacting protein (PAPIN) and ERBIN, in epithelial cells.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12370826","citation_count":40,"is_preprint":false},{"pmid":"22965878","id":"PMC_22965878","title":"Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22965878","citation_count":39,"is_preprint":false},{"pmid":"19339549","id":"PMC_19339549","title":"Targeting of p0071 to the midbody depends on KIF3.","date":"2009","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/19339549","citation_count":33,"is_preprint":false},{"pmid":"23640939","id":"PMC_23640939","title":"p0071/PKP4, a multifunctional protein coordinating cell adhesion with cytoskeletal organization.","date":"2013","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23640939","citation_count":31,"is_preprint":false},{"pmid":"24062571","id":"PMC_24062571","title":"FMRP regulates actin filament organization via the armadillo protein p0071.","date":"2013","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24062571","citation_count":26,"is_preprint":false},{"pmid":"32541000","id":"PMC_32541000","title":"Kir2.1 Interactome Mapping Uncovers PKP4 as a Modulator of the Kir2.1-Regulated Inward Rectifier Potassium Currents.","date":"2020","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/32541000","citation_count":26,"is_preprint":false},{"pmid":"19005682","id":"PMC_19005682","title":"Protein p0071, a major plaque protein of non-desmosomal adhering junctions, is a selective cell-type marker.","date":"2008","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/19005682","citation_count":25,"is_preprint":false},{"pmid":"17264675","id":"PMC_17264675","title":"Beyond regulation of cell adhesion: local control of RhoA at the cleavage furrow by the p0071 catenin.","date":"2007","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/17264675","citation_count":22,"is_preprint":false},{"pmid":"24163434","id":"PMC_24163434","title":"The armadillo protein p0071 is involved in Rab11-dependent recycling.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24163434","citation_count":12,"is_preprint":false},{"pmid":"28808088","id":"PMC_28808088","title":"The armadillo protein p0071 controls KIF3 motor transport.","date":"2017","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/28808088","citation_count":9,"is_preprint":false},{"pmid":"29768670","id":"PMC_29768670","title":"Patients affected by a new variant of endemic pemphigus foliaceus have autoantibodies colocalizing with MYZAP, p0071, desmoplakins 1-2 and ARVCF, causing renal damage.","date":"2018","source":"Clinical and experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/29768670","citation_count":8,"is_preprint":false},{"pmid":"11206135","id":"PMC_11206135","title":"p0071, a member of the armadillo multigene family, is a constituent of sarcomeric I-bands in human skeletal muscle.","date":"2000","source":"Journal of muscle research and cell motility","url":"https://pubmed.ncbi.nlm.nih.gov/11206135","citation_count":6,"is_preprint":false},{"pmid":"29152726","id":"PMC_29152726","title":"Autoantibodies to full body vascular cell junctions colocalize with MYZAP, ARVCF, desmoplakins I and II and p0071 in endemic pemphigus in Colombia, South America.","date":"2017","source":"International journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/29152726","citation_count":6,"is_preprint":false},{"pmid":"37795382","id":"PMC_37795382","title":"Degradation of p0071 and p120-catenin during adherens junction disassembly by Leptospira interrogans.","date":"2023","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/37795382","citation_count":5,"is_preprint":false},{"pmid":"19830446","id":"PMC_19830446","title":"Protein p0071, an armadillo plaque protein of adherens junctions, is predominantly expressed in distal renal tubules.","date":"2009","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19830446","citation_count":5,"is_preprint":false},{"pmid":"29034528","id":"PMC_29034528","title":"Patients with a new variant of endemic pemphigus foliaceus have autoantibodies against arrector pili muscle, colocalizing with MYZAP, p0071, desmoplakins 1 and 2 and ARVCF.","date":"2017","source":"Clinical and experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/29034528","citation_count":5,"is_preprint":false},{"pmid":"28898462","id":"PMC_28898462","title":"p0071 interacts with E-cadherin in the cytoplasm so as to promote the invasion and metastasis of non-small cell lung cancer.","date":"2017","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/28898462","citation_count":4,"is_preprint":false},{"pmid":"35899599","id":"PMC_35899599","title":"Patterns of Antinuclear Antibodies in a New Variant of Endemic Pemphigus in El Bagre, Colombia, Colocalizing with Antigens against MIZAP, ARVCF, p0071, and Desmoplakins I and II.","date":"2022","source":"The journal of applied laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35899599","citation_count":2,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.14.659701","title":"Two δ-Catenins, Plakophilin 4 and p120, Promote Formation of Distinct Types of Adherens Junctions","date":"2025-06-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.14.659701","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16252,"output_tokens":4600,"usd":0.058878,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12592,"output_tokens":4033,"usd":0.081892,"stage2_stop_reason":"end_turn"},"total_usd":0.14077,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"p0071 (PKP4) was cloned and identified as a new armadillo family member with a central armadillo repeat region (10 repeats); it localizes at cell-cell borders and is expressed in the desmosomal plaque of some cultured epithelial cells, suggesting a role as an accessory component of adhesion plaques.\",\n      \"method\": \"cDNA cloning, antibody generation, immunolocalization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — initial cloning and localization study; single lab but multiple methods (cloning, antibodies, immunofluorescence)\",\n      \"pmids\": [\"8937994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The C-terminal fragment of presenilin 1 directly binds to p0071; nine out of ten armadillo repeats in p0071 are essential for mediating this interaction.\",\n      \"method\": \"Yeast two-hybrid system, domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid with domain mapping; single lab, single method\",\n      \"pmids\": [\"10092585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PAPIN (a multi-PDZ scaffolding protein) interacts with p0071 via its second PDZ domain; PAPIN and p0071 colocalize at cell-cell junctions in epithelial cells, suggesting PAPIN connects junction components to p0071.\",\n      \"method\": \"Yeast two-hybrid, co-localization immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus co-localization; single lab, two orthogonal methods\",\n      \"pmids\": [\"10896674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The armadillo repeat domain of p0071 directly binds to VE-cadherin at the same region used by p120; overexpression of p0071 displaces p120 from intercellular junctions. The non-armadillo head domain of p0071 binds desmoplakin. p0071 is required to couple VE-cadherin to desmoplakin in cotransfection assays.\",\n      \"method\": \"Yeast two-hybrid deletion analysis, site-directed mutagenesis, transient expression co-localization, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — yeast two-hybrid domain mapping with mutagenesis, co-IP, and functional displacement assay; multiple orthogonal methods in single study\",\n      \"pmids\": [\"12426320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ERBIN interacts with p0071 in vivo; the ERBIN PDZ domain binds the COOH-terminal PDZ-binding sequence of p0071. ERBIN colocalizes with p0071 at cell-cell contact regions in polarized MDCK cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus endogenous co-IP; single lab, two orthogonal methods\",\n      \"pmids\": [\"12047349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"p0071 localization at cell-cell contacts is independent of PAPIN and ERBIN; PAPIN, p0071, and ERBIN form a complex in 293T cells.\",\n      \"method\": \"Co-immunoprecipitation, calcium-switch assay, immunofluorescence\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus localization experiments; single lab, two orthogonal methods\",\n      \"pmids\": [\"12370826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The head domain of p0071 is sufficient for desmosomal targeting and interacts with desmocollin 3a and desmoplakin; the armadillo repeat domain associates with non-desmosomal (classical) cadherins and enhances their membrane association; the tail domain localizes to the nucleus and associates with desmosomes; both head and armadillo repeat domains interact with plakoglobin at different binding sites.\",\n      \"method\": \"Yeast two-hybrid, membrane targeting (mom) assay, domain deletion constructs, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain dissection with multiple yeast two-hybrid and functional membrane targeting assays; multiple orthogonal methods, replicated across domains\",\n      \"pmids\": [\"12615965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"p0071 localizes to the midbody during cytokinesis and is essential for cell division; knockdown and overexpression of p0071 cause cytokinesis defects (multinucleated cells, apoptosis) through deregulation of RhoA activity. p0071 physically associates with RhoA and with the Rho-GEF Ect2; both p0071 and Ect2 are required together for full RhoA activation at the contractile ring.\",\n      \"method\": \"siRNA knockdown, overexpression, immunofluorescence midbody localization, co-immunoprecipitation with RhoA and Ect2, RhoA activity assays (G-LISA/pulldown)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IPs, RhoA activity assays, KD/OE phenotype with defined cellular readout; multiple orthogonal methods in a high-quality study\",\n      \"pmids\": [\"17115030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p0071 acts as a scaffold at the cleavage furrow to spatiotemporally regulate RhoA by interacting with both RhoA and the Rho-GEF Ect2; unlike p120ctn, p0071 is recruited to the cleavage furrow/midbody and controls local RhoA activation during cytokinesis.\",\n      \"method\": \"Review/commentary synthesizing co-IP, RhoA activity assay, and KD data from Wolf et al. 2006\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — synthesis of previously published co-IP and activity data; no new primary experiments presented\",\n      \"pmids\": [\"17264675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"p0071 targeting to the midbody during cytokinesis is mediated by the kinesin-II family member KIF3B; p0071 interacts with KIF3B, and KIF3B knockdown prevents p0071 midbody recruitment, reduces actin and phospho-myosin light chain at the midbody, and decreases active RhoA during cytokinesis. A p0071-MKLP1 motor domain fusion rescues RhoA activation in KIF3B-deficient cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, rescue with fusion protein, immunofluorescence, RhoA activity assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, KD with defined phenotype, and domain fusion rescue experiment; multiple orthogonal methods\",\n      \"pmids\": [\"19339549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Folliculin (FLCN) physically interacts with p0071; co-downregulation of FLCN or p0071 causes increased cell-cell adhesion and disruption of cell polarity in 3D lumen-forming assays. FLCN positively regulates RhoA and ROCK activity, consistent with p0071's known function.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, cell-based adhesion assays, 3D lumen assay, RhoA/ROCK activity measurement, in vivo mouse K14-Cre Bhd knockout\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus co-IP plus functional cell assays plus in vivo mouse model; multiple orthogonal methods\",\n      \"pmids\": [\"23139756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Folliculin interacts with p0071 and colocalizes at cell junctions and at the midbody during cytokinesis; folliculin deficiency increases RhoA expression and activity, causes disordered cytokinesis, and leads to tight junction defects and E-cadherin mislocalization in renal tubular cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization, RhoA activity assay, ROCK inhibitor rescue, siRNA knockdown\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid, co-IP, RhoA activity assays, functional rescue with ROCK inhibitor; independently replicated FLCN-p0071 interaction (two labs)\",\n      \"pmids\": [\"22965878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FMRP suppresses translation of the p0071 mRNA in a 3'-UTR-dependent manner; loss of FMRP leads to elevated p0071 protein levels, reorganized actin cytoskeleton (reduced stress fibers, lower F/G-actin ratio), and impaired neurite outgrowth; knockdown of p0071 in FMRP-deficient cells rescues the actin phenotype, while p0071 overexpression in FMRP-expressing cells mimics it.\",\n      \"method\": \"Fmr1 knockout MEFs, siRNA knockdown, overexpression, 3'-UTR reporter (translation assay), F/G-actin ratio measurement, immunofluorescence, neurite outgrowth assay\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (KO rescue), translational reporter, multiple cellular phenotypes; multiple orthogonal methods in single study\",\n      \"pmids\": [\"24062571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"p0071 interacts preferentially with active (GTP-bound) Rab11a; p0071 depletion causes perinuclear accumulation of Rab11, shifts transferrin receptor recycling from the slow Rab11-dependent to the fast Rab4-dependent pathway, and increases intercellular adhesion. Rab11a depletion increases p0071 recycling to cell contacts, identifying p0071 as a Rab11 cargo.\",\n      \"method\": \"Co-immunoprecipitation with GTP/GDP-loaded Rab11a, siRNA knockdown, transferrin receptor recycling assay, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — GTP-preference co-IP, functional recycling assay, bidirectional KD phenotypes; multiple orthogonal methods\",\n      \"pmids\": [\"24163434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p0071 directly interacts with the KIF3 motor subunit KIF3B and with the kinesin cargo adaptor KAP3 (KIFAP3), acting as a stabilizing linker between KIF3B and KAP3; p0071 knockdown reduces secretion of chromogranin A and MMP9, impairs directional persistence of vesicle movement, and disrupts KIF3-dependent intracellular membrane vesicle transport.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, vesicle tracking, secretion assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP identifying two binding partners, functional vesicle tracking, and secretion assays; multiple orthogonal methods\",\n      \"pmids\": [\"28808088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p0071 interacts with E-cadherin in the cytoplasm of NSCLC cells; siRNA-mediated knockdown of p0071 inhibits invasion and migration ability of NSCLC cells and is associated with modulation of RhoA activity.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, invasion/migration assay, RhoA activity assay\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP and siRNA knockdown with functional phenotype; single lab, limited mechanistic depth\",\n      \"pmids\": [\"28898462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PKP4 was identified as a high-confidence proximity interactor of the Kir2.1 potassium channel; patch-clamp analysis validated that PKP4 modulates Kir2.1-controlled inward rectifier potassium currents.\",\n      \"method\": \"BioID proximity labeling, patch-clamp electrophysiology\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID interaction map plus functional patch-clamp validation; single lab, two orthogonal methods\",\n      \"pmids\": [\"32541000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"L. interrogans induces proteolysis of p0071 (and p120-catenin) at adherens junctions; p0071 proteolysis is prevented by the pan-caspase inhibitor Z-VAD-FMK, which also prevents displacement of both armadillo proteins from cell-cell junctions, indicating caspase-dependent degradation of p0071 contributes to E-cadherin destabilization and AJ disassembly.\",\n      \"method\": \"Proteomic analysis, immunofluorescence, chemical inhibitor studies (proteasomal, lysosomal, pan-caspase inhibitors)\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus chemical inhibition dissecting degradation pathway; single lab, two orthogonal approaches\",\n      \"pmids\": [\"37795382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PKP4 (plakophilin 4) promotes formation of lateral spot adherens junctions (AJs) via an α-catenin-independent, cadherin–F-actin interaction mechanism, distinct from the canonical p120-driven AJ type that depends on α-catenin–actin interactions; this establishes that the two δ-catenins drive different cadherin clustering modes and AJ specialization.\",\n      \"method\": \"Overexpression and knockdown in epithelial cells, super-resolution/live imaging of cadherin clustering, actin perturbation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional imaging and genetic perturbation with defined phenotype; preprint, not yet peer-reviewed, single study\",\n      \"pmids\": [\"bio_10.1101_2025.06.14.659701\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PKP4/p0071 is a multifunctional armadillo protein that (1) scaffolds adherens junctions and desmosomes by binding classical cadherins (via its armadillo repeats) and desmosomal proteins (via its head domain), promoting an α-catenin-independent lateral spot AJ type distinct from p120-driven junctions; (2) regulates cytokinesis by localizing to the midbody via KIF3B-dependent transport, where it physically associates with RhoA and the Rho-GEF Ect2 to activate RhoA locally at the contractile ring; (3) controls Rab11-dependent endosomal recycling as both a Rab11 regulator and cargo, linking junction dynamics to membrane trafficking; (4) acts as a stabilizing linker within the KIF3B–KAP3 transport complex to direct secretory vesicle movement; (5) is translationally repressed by FMRP, such that excess p0071 disrupts actin organization and neurite outgrowth; and (6) forms a complex with folliculin (FLCN) to negatively regulate cell-cell adhesion and RhoA signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PKP4 (p0071) is a multifunctional armadillo-family protein that scaffolds intercellular junctions and couples them to actomyosin dynamics and membrane trafficking [#0, #3]. Through its central armadillo repeat domain it binds classical cadherins (VE-cadherin) at the same site used by p120, displacing p120 from junctions and enhancing cadherin membrane association, while its non-armadillo head domain engages desmosomal components (desmoplakin, desmocollin 3a) and plakoglobin, allowing PKP4 to physically couple classical cadherins to the desmosomal plaque [#3, #6]. Beyond static adhesion, PKP4 governs cytokinesis: it localizes to the cleavage furrow and midbody, where it scaffolds RhoA together with the Rho-GEF Ect2 to drive local RhoA activation at the contractile ring, and its loss or excess produces multinucleated cells and division failure [#7]. Delivery of PKP4 to the midbody requires the kinesin-II motor KIF3B, and KIF3B-dependent transport is needed for actin, phospho-myosin, and active RhoA accumulation there [#9]. More broadly, PKP4 acts as a stabilizing linker between KIF3B and the cargo adaptor KAP3 to support directional vesicle transport and secretion [#14], and it both regulates and is carried by Rab11-dependent endosomal recycling, linking junction turnover to membrane recycling and tuning the level of intercellular adhesion [#13]. PKP4 forms a complex with folliculin (FLCN) that negatively regulates cell-cell adhesion and supports RhoA/ROCK signaling [#10, #11], and its abundance is translationally repressed by FMRP, with excess PKP4 reorganizing the actin cytoskeleton and impairing neurite outgrowth [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established PKP4/p0071 as an armadillo-family protein resident at cell-cell borders and adhesion plaques, framing it as a candidate junctional component.\",\n      \"evidence\": \"cDNA cloning, antibody generation, and immunolocalization in cultured epithelial cells\",\n      \"pmids\": [\"8937994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No binding partners identified\", \"Functional role at junctions undefined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified scaffolding partners (PAPIN, presenilin 1, later ERBIN) that connect PKP4 to junctional and PDZ-protein networks, defining its interaction surfaces.\",\n      \"evidence\": \"Yeast two-hybrid with domain mapping and co-localization/co-IP in epithelial and 293T cells\",\n      \"pmids\": [\"10092585\", \"10896674\", \"12047349\", \"12370826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of each interaction at junctions not resolved\", \"Several interactions rest on single-lab two-hybrid/Co-IP\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved PKP4 domain logic, showing the armadillo repeats bind classical cadherins (displacing p120) and the head domain binds desmosomal proteins, establishing PKP4 as a coupler of classical-cadherin and desmosomal adhesion systems.\",\n      \"evidence\": \"Yeast two-hybrid deletion analysis, mutagenesis, membrane-targeting assays, co-IP and displacement assays\",\n      \"pmids\": [\"12426320\", \"12615965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type specificity of cadherin vs desmosomal coupling not mapped\", \"Structural basis of dual head/armadillo plakoglobin binding undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed a non-adhesion role: PKP4 scaffolds RhoA and Ect2 at the midbody to drive local RhoA activation required for cytokinesis, explaining the multinucleation/apoptosis phenotype on perturbation.\",\n      \"evidence\": \"siRNA knockdown, overexpression, midbody immunofluorescence, reciprocal co-IP with RhoA and Ect2, RhoA activity assays\",\n      \"pmids\": [\"17115030\", \"17264675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PKP4 spatially restricts RhoA activation mechanistically unclear\", \"Relationship between junctional and cytokinetic pools not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed how PKP4 reaches the midbody — via KIF3B-mediated transport — linking motor-based delivery to RhoA activation and contractile-ring assembly.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, motor-domain fusion rescue, immunofluorescence, RhoA activity assay\",\n      \"pmids\": [\"19339549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo recognition signal on PKP4 for KIF3B unknown\", \"Whether transport carries RhoA/Ect2 with PKP4 not shown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a PKP4-folliculin complex that negatively regulates cell-cell adhesion while supporting RhoA/ROCK signaling, independently replicated across two labs and an in vivo model.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, 3D lumen and adhesion assays, RhoA/ROCK activity, ROCK-inhibitor rescue, and K14-Cre Bhd knockout mice\",\n      \"pmids\": [\"23139756\", \"22965878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical mechanism by which FLCN-PKP4 tunes RhoA undefined\", \"Disease relevance to FLCN-associated phenotypes not established in this corpus\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected PKP4 to membrane trafficking and translational control: it is both a Rab11 regulator and Rab11 cargo governing recycling-pathway choice, and its abundance is repressed by FMRP with consequences for actin and neurite outgrowth.\",\n      \"evidence\": \"GTP/GDP-loaded Rab11a co-IP, transferrin recycling assays, Fmr1-KO MEFs, 3'-UTR reporter, F/G-actin and neurite assays with epistatic rescue\",\n      \"pmids\": [\"24163434\", \"24062571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How recycling status feeds back on junction assembly mechanistically unclear\", \"FMRP-PKP4 axis tested in MEFs/cell models, not neurons in vivo\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Generalized PKP4's transport role as a stabilizing KIF3B-KAP3 linker for secretory vesicle movement, and extended its RhoA-dependent adhesion function into cancer cell invasion.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, vesicle tracking, secretion assays (chromogranin A, MMP9), and NSCLC invasion/migration with RhoA activity readout\",\n      \"pmids\": [\"28808088\", \"28898462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo selectivity of PKP4-KIF3-KAP3 transport undefined\", \"NSCLC mechanism is single-lab and correlative on RhoA\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded the PKP4 interactome to ion channel regulation, with PKP4 modulating Kir2.1 inward-rectifier potassium currents.\",\n      \"evidence\": \"BioID proximity labeling and patch-clamp electrophysiology\",\n      \"pmids\": [\"32541000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs proximity interaction not distinguished\", \"Physiological context of Kir2.1 modulation unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed PKP4 is a target of pathogen-driven junction disassembly, undergoing caspase-dependent proteolysis that contributes to E-cadherin destabilization.\",\n      \"evidence\": \"Proteomics, immunofluorescence, and pan-caspase/proteasomal/lysosomal inhibitor studies during L. interrogans infection\",\n      \"pmids\": [\"37795382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific caspase and cleavage sites not identified\", \"Whether PKP4 loss is cause or consequence of AJ disassembly not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Distinguished PKP4 from p120 functionally, defining it as a driver of alpha-catenin-independent lateral spot adherens junctions via cadherin-F-actin coupling.\",\n      \"evidence\": \"Overexpression/knockdown, super-resolution and live imaging of cadherin clustering, and actin perturbation (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.14.659701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Molecular basis of the cadherin-F-actin link not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PKP4's distinct functional pools — junctional scaffolding, midbody RhoA control, Rab11 recycling, and KIF3-based transport — are coordinated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking PKP4 trafficking to junction turnover\", \"No structural basis for its multivalent partner switching\", \"In vivo physiological roles beyond cell models largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 6, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 9, 13]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [12, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005911\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13, 15]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 6, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 10, 11]}\n    ],\n    \"complexes\": [\n      \"PKP4-KIF3B-KAP3 transport complex\",\n      \"PKP4-RhoA-Ect2 midbody scaffold\",\n      \"PKP4-FLCN complex\"\n    ],\n    \"partners\": [\n      \"RhoA\",\n      \"ECT2\",\n      \"KIF3B\",\n      \"KIFAP3\",\n      \"FLCN\",\n      \"RAB11A\",\n      \"DSP\",\n      \"JUP\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}