PKP1

PKP1 (plakophilin-1) is a desmosomal plaque protein essential for epidermal cell–cell adhesion that also functions outside the desmosome as a regulator of translation and metabolism. Loss-of-function mutations in PKP1 abolish protein expression, reduce desmosome number, detach keratin intermediate filaments, and cause intraepidermal separation, establishing PKP1 as a structural cornerstone of desmosomal integrity (PMID:15086548, PMID:22384142). RIPK4-mediated phosphorylation of the PKP1 N-terminal domain is required for its function during epidermal differentiation and suppression of epidermal carcinogenesis (PMID:28507225). Beyond adhesion, PKP1 binds the 5′-UTR of MYC mRNA to enhance its translation in a feedforward loop with MYC-driven PKP1 transcription (PMID:35182388), and stabilizes the glycolytic enzyme PFKP by sequestering TRIM21 to prevent PFKP ubiquitination and proteasomal degradation, thereby promoting glycolytic and oxidative metabolism (PMID:40890861).

1. 2004 High

   Whether PKP1 is indispensable for desmosomal adhesion in vivo was resolved: human loss-of-function mutations showed complete absence of plakophilin-1 causes intraepidermal separation and aberrant desmosome ultrastructure, proving PKP1 is required for epidermal cohesion.

   Evidence Mutation analysis, immunostaining, and electron microscopy in skin biopsies from affected families

   PMID:15086548

   Open questions at the time

   • Molecular mechanism by which PKP1 recruits desmosomal components or anchors intermediate filaments was not defined
   • Whether other plakophilins can partially compensate in specific epidermal layers remained unclear
2. 2011 Medium

   PKP1's role beyond structural adhesion was expanded: knockdown in Barrett's esophagus cells increased motility, linking PKP1 loss to a migratory phenotype relevant to cancer progression.

   Evidence siRNA knockdown with cell motility assay and promoter methylation analysis in esophageal cell lines

   PMID:22170739

   Open questions at the time

   • Downstream signaling pathways mediating motility suppression by PKP1 were not identified
   • In vivo validation of motility phenotype was lacking
3. 2012 Medium

   Cross-species conservation of PKP1's desmosomal function was confirmed: a canine PKP1 splice-site mutation phenocopied the human disease with reduced desmosomes and detached keratin filaments.

   Evidence Sequencing, immunostaining, and electron microscopy in affected dog epidermis

   PMID:22384142

   Open questions at the time

   • Single breed/pedigree study; broader allelic series not available
   • Mechanistic basis for filament detachment versus desmosome assembly failure not dissected
4. 2017 High

   How PKP1 is activated during differentiation was answered: RIPK4 was identified as a direct kinase that phosphorylates the PKP1 N-terminal domain, and this phosphorylation is essential for epidermal differentiation and tumor suppression.

   Evidence Phosphoproteomics, kinome library screen, in vitro kinase assay, genome-editing, and mouse genetics

   PMID:28507225

   Open questions at the time

   • Specific phosphoresidues and their individual contributions to differentiation versus adhesion not fully mapped
   • Whether RIPK4-PKP1 axis operates outside epidermis is unknown
5. 2021 Medium

   PKP1's contribution to metastatic circulating tumor cell survival was defined: together with DSC2, elevated PKP1 supports cluster formation under shear stress and activates PI3K/AKT and MEK/ERK survival signaling.

   Evidence Microfluidic circulatory selection, siRNA knockdown, western blot, and mouse metastasis models

   PMID:34586853

   Open questions at the time

   • PKP1's individual contribution versus DSC2 was not isolated
   • Whether PKP1's adhesion or signaling function drives the survival advantage is unresolved
6. 2022 Medium

   A non-desmosomal RNA-regulatory function for PKP1 was established: PKP1 binds the 5′-UTR of MYC mRNA and enhances MYC translation, while MYC transcriptionally activates PKP1, forming a feedforward loop.

   Evidence ChIP, promoter mutagenesis with luciferase, gain/loss-of-function in squamous cell lung cancer lines

   PMID:35182388

   Open questions at the time

   • Direct RNA-binding domain or motif in PKP1 responsible for 5′-UTR interaction not mapped
   • Whether this translational role extends beyond MYC or beyond lung squamous carcinoma is unknown
7. 2025 Medium

   A metabolic regulatory mechanism for PKP1 was uncovered: PKP1 binds TRIM21 and prevents TRIM21-mediated ubiquitination and proteasomal degradation of PFKP, promoting glycolysis and oxidative metabolism in lung squamous cell carcinoma.

   Evidence CRISPR knockout screen, OCR/ECAR metabolic assays, ubiquitination assays, co-immunoprecipitation, and rescue experiments

   PMID:40890861

   Open questions at the time

   • Structural basis of PKP1–TRIM21 interaction not determined
   • Whether this metabolic role is cancer-specific or relevant in normal epithelial physiology is unknown
   • Independent replication in additional cancer types or labs is lacking

• How the desmosomal adhesion, translational regulation, and metabolic stabilization functions of PKP1 are coordinated—and whether they are regulated by distinct post-translational modifications or subcellular pools—remains unresolved.
• No structural model of PKP1 in complex with its diverse binding partners exists
• Whether RIPK4 phosphorylation modulates PKP1's non-desmosomal functions is unknown
• Comprehensive identification of PKP1 RNA targets beyond MYC has not been performed