PKP1

PKP1 (plakophilin-1) is a desmosomal plaque component required for epithelial cohesion and a regulator of epidermal differentiation, with additional roles in squamous carcinoma growth and metastasis (PMID:28507225, PMID:15086548). Complete loss of PKP1 in human and canine epidermis through splice-site mutations abolishes the protein, producing intraepidermal separation, widened intercellular spaces, and abnormal desmosome ultrastructure with detached keratin filaments and redistributed desmoplakin, establishing it as essential for desmosome assembly and epithelial cohesion (PMID:15086548, PMID:22384142). During epidermal differentiation, the kinase RIPK4 directly phosphorylates the N-terminal domain of PKP1, and this phosphorylation is essential for their shared role in differentiation and suppression of epidermal carcinogenesis (PMID:28507225). Beyond adhesion, PKP1 carries out cytoplasmic functions in cancer cells: it enhances MYC protein translation by binding the MYC 5'-UTR with the translation initiation complex while MYC reciprocally transactivates the PKP1 promoter, forming a feedforward loop in squamous lung cancer (PMID:35182388), and it stabilizes the glycolytic enzyme PFKP by binding TRIM21 to block PFKP ubiquitination and proteasomal degradation, with PFKP mediating PKP1-driven proliferation (PMID:40890861). In epithelial cancers, loss of PKP1 increases cell motility (PMID:22170739), whereas high PKP1 expression supports circulating tumor-cell cluster formation, shear-stress resistance, and PI3K/AKT- and integrin/FAK/ERK/ZEB1-mediated metastasis (PMID:34586853).

1. 2004 Medium

   Establishing whether PKP1 is genuinely required for human epidermal integrity, this work showed that complete loss of the protein disrupts desmosome structure and epithelial cohesion.

   Evidence Mutation analysis, immunohistochemistry, and electron microscopy of patient skin biopsies carrying homozygous PKP1 splice-site mutations

   PMID:15086548

   Open questions at the time

   • Does not define which desmosomal partners PKP1 directly binds
   • Mechanism linking plaque loss to intercellular separation not resolved at the molecular level
2. 2011 Medium

   Addressing whether PKP1 loss has consequences beyond adhesion failure, knockdown showed it actively restrains cell migration in epithelial cells.

   Evidence siRNA knockdown and cell motility assays in Barrett's esophagus CP-A and CP-D cell lines

   PMID:22170739

   Open questions at the time

   • Molecular pathway coupling PKP1 loss to increased motility not identified
   • Only two cell lines tested; no in vivo confirmation
3. 2012 Medium

   Confirming the human phenotype was a direct consequence of PKP1 loss, a natural canine model recapitulated the desmosomal and keratin defects.

   Evidence DNA sequencing, immunostaining, electron microscopy, and histopathology of a dog carrying a homozygous PKP1 splice donor mutation

   PMID:22384142

   Open questions at the time

   • Does not address PKP1 regulatory or signaling functions
   • Mechanism of desmoplakin/keratin redistribution unresolved
4. 2017 High

   Identifying an upstream regulator of PKP1, this study showed RIPK4 directly phosphorylates the PKP1 N-terminus and that this is essential for epidermal differentiation and tumor suppression.

   Evidence Quantitative phosphoproteomics, kinome cDNA library screen, genome editing, mouse genetics, and in vivo carcinogenesis models

   PMID:28507225

   Open questions at the time

   • Specific phosphosites and how phosphorylation alters PKP1 function not fully mapped
   • Downstream effectors of phosphorylated PKP1 in differentiation not defined
5. 2021 Medium

   Reframing PKP1 as a metastasis driver, high expression was shown to promote tumor-cell cluster formation, shear-stress resistance, and survival/metastatic signaling.

   Evidence Microfluidic selection of shear-resistant cells, knockdown/overexpression, pathway inhibitor studies, and in vivo metastasis in mice

   PMID:34586853

   Open questions at the time

   • Direct molecular link between PKP1 and the PI3K/AKT and integrin/FAK/ERK pathways not biochemically defined
   • Apparent contrast with loss-of-function promoting motility not reconciled
6. 2022 Medium

   Revealing a non-adhesive cytoplasmic function, PKP1 was shown to enhance MYC translation via 5'-UTR binding while MYC transactivates PKP1, forming a feedforward loop in squamous lung cancer.

   Evidence ChIP, promoter mutagenesis with luciferase assays, and gain/loss-of-function with mRNA/protein analysis

   PMID:35182388

   Open questions at the time

   • Direct PKP1 binding to MYC 5'-UTR not demonstrated by structural or crosslinking methods
   • Components of the initiation complex engaged by PKP1 not identified
7. 2025 Medium

   Extending PKP1's cytoplasmic role to metabolism, it was shown to stabilize the glycolytic enzyme PFKP by binding TRIM21 and blocking PFKP ubiquitination.

   Evidence Genome-wide CRISPR knockout screen, OCR/ECAR metabolic assays, ubiquitination assays, and functional rescue in multiple LUSC cell lines

   PMID:40890861

   Open questions at the time

   • Whether PKP1 sequesters TRIM21 away from PFKP or otherwise inhibits the ligase not resolved
   • Direct binary interactions among PKP1, TRIM21, and PFKP not structurally defined

• How PKP1's desmosomal adhesion role mechanistically integrates with its cytoplasmic functions in translation and metabolism, and how RIPK4 phosphorylation toggles between these roles, remains unresolved.
• No unified model linking adhesion, MYC translation, and PFKP stabilization
• Phosphorylation-dependent switch between adhesive and signaling pools undefined