Affinage

PRICKLE3

Prickle planar cell polarity protein 3 · UniProt O43900

Length
615 aa
Mass
68.6 kDa
Annotated
2026-04-28
22 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRICKLE3 is a planar cell polarity (PCP) scaffold protein that functions in both WNT/PCP signaling and mitochondrial ATP synthase biogenesis. In the WNT/PCP pathway, PRICKLE3 forms asymmetric complexes with VANGL1/2 at anterior cell boundaries, where it stabilizes VANGL proteins at the plasma membrane by shielding them from CK1ε-mediated phosphorylation and RNF43-mediated ubiquitination; this complex formation is regulated by Frizzled3-dependent Vangl2 phosphorylation and requires Par3-mediated apical targeting (PMID:41455754, PMID:34806749, PMID:30256191). PRICKLE3 also interacts with the ATP8 subunit of mitochondrial ATP synthase, and loss-of-function mutations (notably p.Arg53Trp) cause defective ATPase assembly and stability, leading to Leber hereditary optic neuropathy-like retinal ganglion cell degeneration that is synergistically worsened by mitochondrial complex I mutations (PMID:32516135, PMID:35947995). Additionally, PRICKLE3 associates with Wtip at the basal body to regulate ciliogenesis and basal body organization, and in cancer cells it recruits USP9X to deubiquitinate DVL2, thereby activating canonical WNT/β-catenin signaling (PMID:27062996, PMID:40973792).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2015 High

    Establishing that Vangl2/Prickle3 complexes localize apically in intercalating cells and are required for radial intercalation resolved the question of whether Prickle3 plays a functional role in PCP-driven morphogenesis beyond simple polarity readout.

    Evidence Morpholino loss-of-function, immunofluorescence, and live imaging of multiciliated cell intercalation in Xenopus ectoderm

    PMID:26079437

    Open questions at the time
    • Mechanism by which the Vangl2/Prickle3 complex drives intercalation not defined
    • Direct binding interface between Vangl2 and Prickle3 uncharacterized
  2. 2016 High

    Demonstrating that Prickle3 localizes to the basal body, interacts with Wtip, and is required for basal body-associated γ-tubulin/Nedd1 recruitment and ciliogenesis established a cilia-organizing function for Prickle3 beyond classical PCP.

    Evidence Co-immunoprecipitation (Pk3–Wtip), morpholino knockdown, immunofluorescence, and live imaging in Xenopus GRP cells

    PMID:27062996

    Open questions at the time
    • Whether Wtip is a direct or indirect binding partner is not resolved by reciprocal assay
    • Mechanism linking Prickle3 to γ-tubulin recruitment unknown
  3. 2016 High

    Showing that Wnt ligands (Wnt5a, Wnt11, Wnt11b) provide instructive directional cues that orient the Prickle3/Vangl2 complex answered whether Prickle3 polarity is cell-autonomously determined or externally directed.

    Evidence Ectopic Wnt source transplantation, Wnt antagonist treatment, and live imaging of fluorescent PCP fusions in Xenopus ectoderm

    PMID:27658614

    Open questions at the time
    • Receptor-level mechanism transducing the Wnt cue to Prickle3/Vangl2 not identified
    • Whether the same instructive mechanism operates in mammalian tissues untested
  4. 2018 High

    Identifying Par3 as a physical partner that promotes apical localization of Prickle3 and thereby the anterior Vangl2/Prickle3 complex linked apical-basal polarity machinery to planar polarity establishment.

    Evidence Reciprocal Co-IP, proximity biotinylation, dominant-negative overexpression, and neural tube phenotyping in Xenopus

    PMID:30256191

    Open questions at the time
    • Structural basis of Par3–Prickle3 interaction unknown
    • Whether Par3 similarly regulates Prickle1 or Prickle2 localization untested
  5. 2020 High

    Discovering that PRICKLE3 interacts with ATP synthase via ATP8 and that loss-of-function causes ATPase assembly defects and LHON-like retinal degeneration revealed an unexpected mitochondrial role for a PCP protein and established PRICKLE3 as a modifier gene for Leber hereditary optic neuropathy.

    Evidence Co-immunoprecipitation, PRICKLE3 knockdown/knockout cells and mice, ATP synthase assembly assays, retinal ganglion cell phenotyping across multiple LHON pedigrees

    PMID:32516135

    Open questions at the time
    • How PRICKLE3 accesses mitochondria (import mechanism) not determined
    • Whether PRICKLE3 affects other OXPHOS complexes not tested
    • Structural details of PRICKLE3–ATP8 interaction absent
  6. 2021 High

    Demonstrating that Frizzled3-dependent phosphorylation of Vangl2 inhibits Vangl2–Prickle3 complex formation established a molecular switch controlling PCP complex assembly and explained how Frizzled and Vangl/Prickle complexes are sorted to opposite cell faces.

    Evidence Proximity biotinylation, chemical crosslinking, phospho-mutant Vangl2 analysis in Xenopus neural plate

    PMID:34806749

    Open questions at the time
    • Specific phosphorylation sites on Vangl2 that regulate Prickle3 binding not mapped at residue level
    • Whether this mechanism is conserved in mammals not directly shown
  7. 2023 Medium

    Confirming synergistic pathogenicity of PRICKLE3 p.Arg53Trp with mitochondrial ND4 11778G>A in patient-derived iPSC retinal ganglion cells validated the two-hit model for LHON penetrance involving nuclear PRICKLE3 and mitochondrial complex I mutations.

    Evidence iPSC differentiation to RGC-like cells, electrophysiology, ATP content, and apoptosis assays

    PMID:35947995

    Open questions at the time
    • Single lab replication of original finding
    • Therapeutic rescue of PRICKLE3-related mitochondrial defect not attempted
  8. 2025 High

    Defining PRICKLE3's mechanism at the plasma membrane — protecting VANGL1/2 from CK1ε phosphorylation and RNF43-mediated ubiquitination — resolved how PRICKLE3 specifically stabilizes VANGL proteins and distinguished its function from PRICKLE1.

    Evidence MiniTurboID proximity biotinylation/mass spectrometry, stability assays, live imaging in human cells, Xenopus and zebrafish embryos

    PMID:41455754

    Open questions at the time
    • Whether PRICKLE3 directly contacts RNF43 or acts indirectly through CK1ε shielding unclear
    • Stoichiometry of the PRICKLE3–VANGL–CK1ε complex not determined
  9. 2025 Medium

    Showing that PRICKLE3 recruits USP9X to deubiquitinate DVL2 and activate canonical WNT/β-catenin signaling in NSCLC revealed an oncogenic function through a non-PCP WNT branch.

    Evidence Co-immunoprecipitation (PRICKLE3–USP9X–DVL2), knockout/overexpression, in vivo tumor models, ubiquitination and β-catenin reporter assays

    PMID:40973792

    Open questions at the time
    • Single lab; canonical WNT activation role not independently replicated
    • Whether this function is cancer-specific or operates in normal tissues unknown
    • Direct versus bridged interaction between PRICKLE3 and USP9X not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PRICKLE3 is dually targeted to mitochondria and the plasma membrane, and whether its PCP and mitochondrial functions are coordinated or independent, remains unresolved.
  • No mitochondrial targeting sequence or import pathway identified
  • No structural model for any PRICKLE3 complex exists
  • Tissue-specific balance between PCP and mitochondrial roles unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005739 mitochondrion 2 GO:0005886 plasma membrane 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1430728 Metabolism 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
ATP8DVL2PARD3RNF43USP9XVANGL1VANGL2WTIP
Complex memberships
PRICKLE3–ATP synthase (via ATP8)Vangl2/Prickle3 anterior PCP complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 PRICKLE3 physically interacts with ATP synthase via ATP8 subunit (co-immunoprecipitation), and the p.Arg53Trp mutation causes defective assembly, stability, and function of ATP synthase in mitochondria; PRICKLE3 knockdown recapitulates these defects, and Prickle3-knockout mice exhibit pronounced ATPase deficiencies and LHON-like retinal phenotypes. Co-immunoprecipitation, PRICKLE3 knockdown/knockout cells and mice, functional ATP synthase assembly assays, retinal ganglion cell degeneration phenotyping The Journal of clinical investigation High 32516135
2016 In Xenopus gastrocoel roof plate (GRP), Prickle3 is enriched at the basal body of GRP cells but is recruited by Vangl2 to anterior cell borders; Prickle3 loss-of-function disrupts anterior polarization of Vangl2, posterior cilia localization, and cilia growth, with γ-tubulin and Nedd1 no longer associating with the basal body; Prickle3 physically associates with Wtip (Wilms tumor protein 1-interacting protein), which cooperates with Pk3 to regulate ciliogenesis. Loss-of-function (morpholino knockdown), immunofluorescence imaging, co-immunoprecipitation (Pk3–Wtip interaction), live imaging Scientific reports High 27062996
2016 In Xenopus ectoderm, the Prickle3/Vangl2 complex is polarized to anterior cell edges; this polarity is disrupted by Wnt antagonists and redirected by ectopic Wnt5a, Wnt11, or Wnt11b sources, demonstrating that Wnt ligands provide instructive cues for Prickle3/Vangl2 complex orientation. Live imaging of fluorescent PCP protein fusions in Xenopus embryos, Wnt antagonist treatment, ectopic Wnt source transplantation, Wnt11b depletion eLife High 27658614
2015 Vangl2/Prickle3 protein complexes are enriched at the apical domain of intercalating multiciliated cells (MCCs) in Xenopus ectoderm and are essential for MCC intercalatory behavior; Vangl2 or Dishevelled loss-of-function caused tissues to contain more cell layers than normal, indicating a role for this complex in radial cell intercalation. Loss-of-function (morpholino), immunofluorescence, live imaging, genetic epistasis with KIF13B Developmental biology High 26079437
2018 Par3 physically associates with Prickle3, promotes its apical localization in the Xenopus neural plate, and enhances formation of the anterior apical PCP complex (Vangl2/Prickle3); overexpression of a Prickle3-binding Par3 fragment disrupts PCP, and Par3 interference inhibits asymmetric PCP protein distribution and causes neural tube defects. Co-immunoprecipitation (Par3–Prickle3), proximity biotinylation assay in Xenopus embryos, dominant-negative overexpression, live imaging eLife High 30256191
2021 Frizzled3 (Fz3) inhibits Vangl2–Prickle3 association in vivo through Fz3-dependent Vangl2 phosphorylation; a nonphosphorylatable Vangl2 mutant forms a complex with Prickle3 that fails to polarize in the neural plate, establishing that Frizzled3-mediated phosphorylation of Vangl2 regulates Vangl2–Prickle3 complex formation and localization. Proximity biotinylation, chemical crosslinking, phospho-mutant Vangl2 analysis, loss-of-function in Xenopus neural plate Journal of cell science High 34806749
2021 PCP is progressively acquired in the Xenopus neural plate and requires a planar cue from the dorsal blastopore lip, as demonstrated by imaging of Vangl2 and Prickle3 polarity following tissue transplantations; PCP is not instructed by a preexisting egg polarity gradient. Tissue transplantation, live imaging of Vangl2/Prickle3 fluorescent fusions in Xenopus embryos Biology open Medium 34259326
2025 PRICKLE3 localizes at the plasma membrane and associates with VANGL1 and VANGL2 (core WNT/PCP proteins); it selectively stabilizes VANGL1/2 by protecting them from Casein kinase 1ε (CK1ε)-mediated phosphorylation, and modulates an interaction network involving VANGL1/2, CK1ε, and ubiquitin ligase RNF43 to reduce VANGL ubiquitination and increase VANGL accumulation at the plasma membrane; these effects are specific to PRICKLE3 and not shared by PRICKLE1. Enhanced proximity biotinylation (miniTurboID) + mass spectrometry, immunoblotting, live imaging, functional stability assays, inducible expression system in human cells and Xenopus/zebrafish embryos Communications biology High 41455754
2025 PRICKLE3 interacts with USP9X and DVL2; PRICKLE3–DVL2 interaction enhances β-catenin phosphorylation at serine 675 for β-catenin nuclear translocation; PRICKLE3 interacts with USP9X to inhibit DVL2 ubiquitination, thereby stabilizing DVL2 and activating canonical WNT signaling to promote NSCLC progression. Co-immunoprecipitation (PRICKLE3–USP9X–DVL2), PRICKLE3 overexpression/knockout cells, in vivo tumor models, ubiquitination assays, β-catenin reporter assays Oncogene Medium 40973792
2023 PRICKLE3 p.Arg53Trp mutation, when combined with mitochondrial ND4 11778G>A mutation in patient-derived iPSC-differentiated retinal ganglion cells, causes greater defects in RGC morphology, electrophysiology, ATP content, and apoptosis than either single mutation alone, confirming the synergistic interaction between PRICKLE3 (ATPase biogenesis) and complex I dysfunction. iPSC differentiation to RGC-like cells, electrophysiology, ATP content measurement, apoptosis assays, morphological quantification Human molecular genetics Medium 35947995
2026 SPEM2 interacts with VANGL2, PRICKLE3, and DVL3 (co-immunoprecipitation) to maintain spermiation and cell polarity; the transmembrane region of SPEM2 is the key domain for binding VANGL2, placing PRICKLE3 in a PCP complex required for sperm head morphology and cytoplasmic removal during spermatid release. Co-immunoprecipitation, domain-deletion analysis (transmembrane region), Spem2-knockout mice with defined spermiation defects Biology of reproduction Low 42028965

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Identification and characterization of human PRICKLE1 and PRICKLE2 genes as well as mouse Prickle1 and Prickle2 genes homologous to Drosophila tissue polarity gene prickle. International journal of molecular medicine 159 12525887
2016 Wnt proteins can direct planar cell polarity in vertebrate ectoderm. eLife 63 27658614
2020 PRICKLE3 linked to ATPase biogenesis manifested Leber's hereditary optic neuropathy. The Journal of clinical investigation 57 32516135
2015 The involvement of PCP proteins in radial cell intercalations during Xenopus embryonic development. Developmental biology 44 26079437
2020 G-Quadruplexes in the Archaea Domain. Biomolecules 38 32967357
1997 Sequence-based exon prediction around the synaptophysin locus reveals a gene-rich area containing novel genes in human proximal Xp. Genomics 35 9344658
2018 Par3 interacts with Prickle3 to generate apical PCP complexes in the vertebrate neural plate. eLife 33 30256191
2016 Prickle3 synergizes with Wtip to regulate basal body organization and cilia growth. Scientific reports 31 27062996
2023 Abnormal morphology and function in retinal ganglion cells derived from patients-specific iPSCs generated from individuals with Leber's hereditary optic neuropathy. Human molecular genetics 15 35947995
2021 Frizzled3 inhibits Vangl2-Prickle3 association to establish planar cell polarity in the vertebrate neural plate. Journal of cell science 13 34806749
2020 Diversity and Host Interactions Among Virulent and Temperate Baltic Sea Flavobacterium Phages. Viruses 13 32019073
2015 Localization of Core Planar Cell Polarity Proteins, PRICKLEs, in Ameloblasts of Rat Incisors: Possible Regulation of Enamel Rod Decussation. Acta histochemica et cytochemica 13 26175546
2021 The dorsal blastopore lip is a source of signals inducing planar cell polarity in the Xenopus neural plate. Biology open 11 34259326
2023 Construction of T cell exhaustion model for predicting survival and immunotherapy effect of bladder cancer based on WGCNA. Frontiers in oncology 6 37324016
2022 Analysis of Planar Cell Polarity Complexes by Proximity Biotinylation in Xenopus Embryos. Methods in molecular biology (Clifton, N.J.) 5 35147937
2022 Imaging Planar Cell Polarity Proteins in Xenopus Neuroectoderm. Methods in molecular biology (Clifton, N.J.) 4 35147941
2023 Leber's hereditary optic neuropathy: Update on the novel genes and therapeutic options. Journal of the Chinese Medical Association : JCMA 3 38016117
2021 C-Jun N-terminal kinase (JNK) pathway activation is essential for dental papilla cells polarization. PloS one 3 33770099
2024 Integrative analysis of blood transcriptome profiles in small-cell lung cancer patients for identification of novel chemotherapy resistance-related biomarkers. Frontiers in immunology 2 38957470
2025 PRICKLE3-USP9X interaction-mediated DVL2 deubiquitination promotes the progression of non-small cell lung cancer via canonical WNT pathway. Oncogene 1 40973792
2026 SPEM2 deficiency disrupts spermiation leading to oligoasthenoteratozoospermia and male infertility†. Biology of reproduction 0 42028965
2025 PRICKLE3 protects VANGL proteins from CK1-mediated phosphorylation and RNF43-mediated degradation. Communications biology 0 41455754