PKP3

PKP3 is a plakophilin family member that functions beyond cell adhesion as a signaling intermediate linking Wnt, MAPK, and necroptosis pathways. PKP3 associates with the β-catenin destruction complex components GSK3β and Axin, is stabilized and translocates to the nucleus upon Wnt ligand stimulation, and activates Wnt-responsive transcription (PMID:34058472). PKP3 also activates downstream MAPK/p38 and mTOR signaling to promote cell proliferation, invasion, and ERCC1 expression (PMID:30527804, PMID:38200443, PMID:37420272), and positively regulates RIPK3/MLKL-dependent necroptosis (PMID:40116080). PKP3 expression is controlled by promoter/gene-body methylation (PMID:34415821) and is post-transcriptionally suppressed by miR-10b-5p, which directly targets its 3′-UTR (PMID:40116080), and by miR-149 (PMID:30144176).

1. 2018 Low

   Establishing that PKP3 is not merely a structural desmosomal protein but an upstream activator of mTOR signaling that promotes cancer cell proliferation, invasion, and autophagy regulation in ovarian cancer.

   Evidence siRNA knockdown and overexpression with pathway inhibitors and proliferation/invasion assays in ovarian cancer cells

   PMID:30527804

   Open questions at the time

   • No direct biochemical interaction between PKP3 and MAPK/mTOR components was demonstrated
   • Single cell-line context (ovarian cancer); generalizability unclear
   • Mechanism by which PKP3 engages MAPK pathway not resolved
2. 2018 Low

   Identifying PKP3 as a downstream target of miR-149 whose suppression by the carcinogen DNP promotes nasopharyngeal carcinoma cell migration and invasion, providing the first evidence for miRNA-mediated PKP3 regulation.

   Evidence miR-149 inhibitor rescue experiments and western blot in NPC cell lines treated with DNP

   PMID:30144176

   Open questions at the time

   • Direct binding of miR-149 to the PKP3 3′-UTR was not validated by luciferase reporter assay
   • Mechanism linking PKP3 loss to enhanced invasion not delineated
3. 2021 Medium

   Revealing that PKP3 is a novel component of the canonical Wnt signaling cascade: it associates with the GSK3β/Axin destruction complex, is stabilized by Wnt ligand, translocates to the nucleus, and activates Wnt-responsive transcription—establishing PKP3 as a Wnt-responsive nuclear effector analogous to β-catenin.

   Evidence Co-immunoprecipitation of PKP3 with GSK3β and Axin, Wnt luciferase reporter assay, nuclear localization imaging upon Wnt stimulation or dominant-active LRP6

   PMID:34058472

   Open questions at the time

   • Whether PKP3 directly binds TCF/LEF transcription factors in the nucleus is unknown
   • Not confirmed whether PKP3 is a direct phosphorylation substrate of GSK3β
   • Single lab study; independent replication lacking
4. 2021 Medium

   Demonstrating that a gene-body sequence within PKP3 possesses methylation-dependent promoter activity in lung epithelial cells, linking epigenetic regulation to PKP3 transcriptional control.

   Evidence Luciferase reporter assays comparing methylated vs. unmethylated PKP3 gene-body constructs in lung epithelial cells; bisulfite sequencing in cystic fibrosis patient blood

   PMID:34415821

   Open questions at the time

   • Whether gene-body methylation regulates endogenous PKP3 protein levels in vivo is not shown
   • Transcription factors responsive to the methylation state of this region are unidentified
5. 2023 Low

   Extending the PKP3–MAPK axis by showing PKP3 augments ERCC1 expression through MAPK activation in ovarian granulosa cells, and that PKP3 promoter methylation controls this signaling cascade.

   Evidence PKP3 overexpression/knockdown with ERCC1 and MAPK western blot, promoter methylation analysis in granulosa cells

   PMID:37420272

   Open questions at the time

   • No direct biochemical interaction between PKP3 and any MAPK component demonstrated
   • Single cell type; relevance to other tissues unclear
6. 2024 Low

   Placing PKP3 downstream of FERMT1 and upstream of p38 MAPK in an epistatic signaling axis that drives NSCLC migration and invasion, specifying p38 as the MAPK branch regulated by PKP3.

   Evidence siRNA knockdown of PKP3 reversing FERMT1-induced p38 MAPK activation; Transwell assays in NSCLC cells

   PMID:38200443

   Open questions at the time

   • Direct physical interaction between PKP3 and p38 MAPK or its upstream kinases not shown
   • Whether FERMT1 directly regulates PKP3 transcription or protein stability is unknown
7. 2025 Medium

   Establishing PKP3 as a positive regulator of RIPK3/MLKL-dependent necroptosis and validating miR-10b-5p as a direct suppressor of PKP3 via its 3′-UTR, linking PKP3 loss to necroptosis evasion and tumor growth in LUAD.

   Evidence Dual luciferase reporter assay confirming miR-10b-5p targeting of PKP3 3′-UTR; PKP3 knockdown phenocopying miR-10b-5p overexpression; RIPK3/MLKL western blot; xenograft model

   PMID:40116080

   Open questions at the time

   • Whether PKP3 directly binds RIPK3 or acts through an intermediary is unknown
   • Mechanism by which PKP3 activates the necroptosis cascade not resolved
   • Single cancer type studied (LUAD)
8. 2025 Low

   Identifying a circFOXK2/miR-328-5p/PKP3 regulatory axis that promotes NSCLC proliferation and invasion, adding another miRNA-mediated layer of PKP3 post-transcriptional control.

   Evidence Dual luciferase assay for circFOXK2–miR-328-5p interaction; qRT-PCR and functional assays in NSCLC cells

   PMID:41351372

   Open questions at the time

   • Direct targeting of PKP3 3′-UTR by miR-328-5p not independently validated by luciferase assay
   • Whether circFOXK2 regulation of PKP3 occurs in non-cancer contexts is unknown

• How PKP3 biochemically activates MAPK/p38 and RIPK3/MLKL pathways—whether through direct binding or adaptor-mediated mechanisms—remains unresolved, as does the structural basis for its interaction with the Wnt destruction complex and whether it acts as a transcriptional co-activator in the nucleus.
• No structural or reconstituted biochemical data for PKP3 interaction with any signaling partner
• Whether PKP3 desmosomal and signaling functions are mutually exclusive or coordinated is unknown
• No in vivo genetic models (knockout mice) characterizing PKP3 physiological function