Affinage

PKP4

Plakophilin-4 · UniProt Q99569

Length
1192 aa
Mass
131.9 kDa
Annotated
2026-06-10
27 papers in source corpus 19 papers cited in narrative 19 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1996 Medium

    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

    PMID:8937994

    Open questions at the time
    • No binding partners identified
    • Functional role at junctions undefined
  2. 2000 Medium

    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

    PMID:10092585 PMID:10896674 PMID:12047349 PMID:12370826

    Open questions at the time
    • Functional consequence of each interaction at junctions not resolved
    • Several interactions rest on single-lab two-hybrid/Co-IP
  3. 2003 High

    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

    PMID:12426320 PMID:12615965

    Open questions at the time
    • Cell-type specificity of cadherin vs desmosomal coupling not mapped
    • Structural basis of dual head/armadillo plakoglobin binding undefined
  4. 2006 High

    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

    PMID:17115030 PMID:17264675

    Open questions at the time
    • How PKP4 spatially restricts RhoA activation mechanistically unclear
    • Relationship between junctional and cytokinetic pools not defined
  5. 2009 High

    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

    PMID:19339549

    Open questions at the time
    • Cargo recognition signal on PKP4 for KIF3B unknown
    • Whether transport carries RhoA/Ect2 with PKP4 not shown
  6. 2012 High

    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

    PMID:22965878 PMID:23139756

    Open questions at the time
    • Direct biochemical mechanism by which FLCN-PKP4 tunes RhoA undefined
    • Disease relevance to FLCN-associated phenotypes not established in this corpus
  7. 2013 High

    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

    PMID:24062571 PMID:24163434

    Open questions at the time
    • How recycling status feeds back on junction assembly mechanistically unclear
    • FMRP-PKP4 axis tested in MEFs/cell models, not neurons in vivo
  8. 2017 High

    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

    PMID:28808088 PMID:28898462

    Open questions at the time
    • Cargo selectivity of PKP4-KIF3-KAP3 transport undefined
    • NSCLC mechanism is single-lab and correlative on RhoA
  9. 2020 Medium

    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

    PMID:32541000

    Open questions at the time
    • Direct vs proximity interaction not distinguished
    • Physiological context of Kir2.1 modulation unknown
  10. 2023 Medium

    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

    PMID:37795382

    Open questions at the time
    • Specific caspase and cleavage sites not identified
    • Whether PKP4 loss is cause or consequence of AJ disassembly not fully resolved
  11. 2025 Medium

    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)

    PMID:bio_10.1101_2025.06.14.659701

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Molecular basis of the cadherin-F-actin link not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-1500931 Cell-Cell communication 3 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
DSPECT2FLCNJUPKIF3BKIFAP3RAB11ARHOA
Complex memberships
PKP4-FLCN complexPKP4-KIF3B-KAP3 transport complexPKP4-RhoA-Ect2 midbody scaffold

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 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. cDNA cloning, antibody generation, immunolocalization Journal of cell science Medium 8937994
1999 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. Yeast two-hybrid system, domain deletion analysis The Journal of biological chemistry Medium 10092585
2000 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. Yeast two-hybrid, co-localization immunofluorescence The Journal of biological chemistry Medium 10896674
2002 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. Yeast two-hybrid deletion analysis, site-directed mutagenesis, transient expression co-localization, co-immunoprecipitation The Journal of biological chemistry High 12426320
2002 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. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization Genes to cells Medium 12047349
2002 p0071 localization at cell-cell contacts is independent of PAPIN and ERBIN; PAPIN, p0071, and ERBIN form a complex in 293T cells. Co-immunoprecipitation, calcium-switch assay, immunofluorescence Oncogene Medium 12370826
2003 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. Yeast two-hybrid, membrane targeting (mom) assay, domain deletion constructs, immunofluorescence Journal of cell science High 12615965
2006 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. siRNA knockdown, overexpression, immunofluorescence midbody localization, co-immunoprecipitation with RhoA and Ect2, RhoA activity assays (G-LISA/pulldown) Nature cell biology High 17115030
2007 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. Review/commentary synthesizing co-IP, RhoA activity assay, and KD data from Wolf et al. 2006 Cell cycle Medium 17264675
2009 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. Co-immunoprecipitation, siRNA knockdown, rescue with fusion protein, immunofluorescence, RhoA activity assay Journal of cell science High 19339549
2012 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. Yeast two-hybrid, co-immunoprecipitation, cell-based adhesion assays, 3D lumen assay, RhoA/ROCK activity measurement, in vivo mouse K14-Cre Bhd knockout PloS one High 23139756
2012 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. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization, RhoA activity assay, ROCK inhibitor rescue, siRNA knockdown Human molecular genetics High 22965878
2013 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. Fmr1 knockout MEFs, siRNA knockdown, overexpression, 3'-UTR reporter (translation assay), F/G-actin ratio measurement, immunofluorescence, neurite outgrowth assay RNA High 24062571
2013 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. Co-immunoprecipitation with GTP/GDP-loaded Rab11a, siRNA knockdown, transferrin receptor recycling assay, immunofluorescence Journal of cell science High 24163434
2017 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. Co-immunoprecipitation, siRNA knockdown, vesicle tracking, secretion assays Journal of cell science High 28808088
2017 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. Co-immunoprecipitation, siRNA knockdown, invasion/migration assay, RhoA activity assay Molecular carcinogenesis Medium 28898462
2020 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. BioID proximity labeling, patch-clamp electrophysiology Molecular & cellular proteomics Medium 32541000
2023 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. Proteomic analysis, immunofluorescence, chemical inhibitor studies (proteasomal, lysosomal, pan-caspase inhibitors) Frontiers in cellular and infection microbiology Medium 37795382
2025 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. Overexpression and knockdown in epithelial cells, super-resolution/live imaging of cadherin clustering, actin perturbation assays bioRxivpreprint Medium bio_10.1101_2025.06.14.659701

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Cloning and characterization of a new armadillo family member, p0071, associated with the junctional plaque: evidence for a subfamily of closely related proteins. Journal of cell science 124 8937994
2002 ERBIN associates with p0071, an armadillo protein, at cell-cell junctions of epithelial cells. Genes to cells : devoted to molecular & cellular mechanisms 67 12047349
2006 The armadillo protein p0071 regulates Rho signalling during cytokinesis. Nature cell biology 64 17115030
2003 Targeting of p0071 to desmosomes and adherens junctions is mediated by different protein domains. Journal of cell science 64 12615965
2003 Immunohistochemical localization of plakophilins (PKP1, PKP2, PKP3, and p0071) in primary oropharyngeal tumors: correlation with clinical parameters. Human pathology 62 12827610
2012 Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion. PloS one 60 23139756
2002 The Armadillo family protein p0071 is a VE-cadherin- and desmoplakin-binding protein. The Journal of biological chemistry 57 12426320
2000 PAPIN. A novel multiple PSD-95/Dlg-A/ZO-1 protein interacting with neural plakophilin-related armadillo repeat protein/delta-catenin and p0071. The Journal of biological chemistry 57 10896674
1999 Direct interaction of Alzheimer's disease-related presenilin 1 with armadillo protein p0071. The Journal of biological chemistry 57 10092585
2002 Localization of p0071-interacting proteins, plakophilin-related armadillo-repeat protein-interacting protein (PAPIN) and ERBIN, in epithelial cells. Oncogene 40 12370826
2012 Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Human molecular genetics 39 22965878
2009 Targeting of p0071 to the midbody depends on KIF3. Journal of cell science 33 19339549
2013 p0071/PKP4, a multifunctional protein coordinating cell adhesion with cytoskeletal organization. Biological chemistry 31 23640939
2020 Kir2.1 Interactome Mapping Uncovers PKP4 as a Modulator of the Kir2.1-Regulated Inward Rectifier Potassium Currents. Molecular & cellular proteomics : MCP 26 32541000
2013 FMRP regulates actin filament organization via the armadillo protein p0071. RNA (New York, N.Y.) 26 24062571
2008 Protein p0071, a major plaque protein of non-desmosomal adhering junctions, is a selective cell-type marker. Cell and tissue research 25 19005682
2007 Beyond regulation of cell adhesion: local control of RhoA at the cleavage furrow by the p0071 catenin. Cell cycle (Georgetown, Tex.) 22 17264675
2013 The armadillo protein p0071 is involved in Rab11-dependent recycling. Journal of cell science 12 24163434
2017 The armadillo protein p0071 controls KIF3 motor transport. Journal of cell science 9 28808088
2018 Patients affected by a new variant of endemic pemphigus foliaceus have autoantibodies colocalizing with MYZAP, p0071, desmoplakins 1-2 and ARVCF, causing renal damage. Clinical and experimental dermatology 8 29768670
2017 Autoantibodies to full body vascular cell junctions colocalize with MYZAP, ARVCF, desmoplakins I and II and p0071 in endemic pemphigus in Colombia, South America. International journal of dermatology 6 29152726
2000 p0071, a member of the armadillo multigene family, is a constituent of sarcomeric I-bands in human skeletal muscle. Journal of muscle research and cell motility 6 11206135
2023 Degradation of p0071 and p120-catenin during adherens junction disassembly by Leptospira interrogans. Frontiers in cellular and infection microbiology 5 37795382
2017 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. Clinical and experimental dermatology 5 29034528
2009 Protein p0071, an armadillo plaque protein of adherens junctions, is predominantly expressed in distal renal tubules. Histochemistry and cell biology 5 19830446
2017 p0071 interacts with E-cadherin in the cytoplasm so as to promote the invasion and metastasis of non-small cell lung cancer. Molecular carcinogenesis 4 28898462
2022 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. The journal of applied laboratory medicine 2 35899599

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