PKP3

PKP3 is a plakophilin-subfamily catenin that functions as a signaling adaptor coupling membrane and cytoplasmic signaling to transcriptional and cell-fate outcomes. It participates in canonical Wnt signaling: PKP3 protein is stabilized by Wnt-ligand or dominant-active LRP6 stimulation and destabilized by the destruction-complex components GSK3β and Axin, with which it physically associates; upon Wnt stimulation it translocates to the nucleus and activates a Wnt transcriptional reporter (PMID:34058472). PKP3 also influences cell proliferation and survival through its post-transcriptional regulation, as it is a direct target of miR-10b-5p and acts to sustain RIPK3/MLKL necroptosis signaling, such that loss of PKP3 promotes proliferation and reduces necroptosis in lung adenocarcinoma (PMID:40116080). PKP3 expression is further controlled epigenetically through a methylation-dependent regulatory sequence in its gene body that drives promoter activity in lung epithelial cells (PMID:34415821). Beyond these axes, direct biochemical mechanisms linking PKP3 to downstream effectors remain incompletely characterized in the available corpus.

1. 2018 Low

   Established that PKP3 levels are subject to microRNA control, framing it as a regulated node rather than a static structural protein, with functional consequences for tumor cell behavior.

   Evidence miR-149 overexpression/inhibitor rescue and Western blot for PKP3 in nasopharyngeal carcinoma cells

   PMID:30144176

   Open questions at the time

   • No direct 3'UTR luciferase validation of miR-149 targeting reported
   • Single lab, single cancer model
   • Mechanism linking PKP3 loss to migration/invasion not biochemically defined
2. 2018 Low

   Addressed how PKP3 influences cell proliferation and invasion, placing it upstream of MAPK-JNK-ERK1/2-mTOR signaling and autophagy.

   Evidence siRNA knockdown and overexpression in ovarian cancer cells with Western blot of pathway components and invasion/proliferation assays

   PMID:30527804

   Open questions at the time

   • Pathway placement inferred from KD/OE, not direct PKP3-MAPK biochemical interaction
   • No reconstitution of the proposed signaling chain
   • Single lab
3. 2021 Medium

   Defined a direct link between PKP3 and canonical Wnt signaling, showing PKP3 is a destruction-complex-regulated factor that enters the nucleus to drive Wnt-responsive transcription.

   Evidence Co-IP with GSK3β and Axin, Wnt-ligand/dominant-active LRP6 stability assays, nuclear localization imaging, and Wnt luciferase reporter

   PMID:34058472

   Open questions at the time

   • Direct nuclear transcriptional targets of PKP3 not identified
   • Single lab
   • Stoichiometry and structural basis of GSK3β/Axin association unknown
4. 2021 Medium

   Showed that PKP3 expression is itself epigenetically controlled, identifying a methylation-dependent regulatory sequence in its gene body active in lung epithelial cells.

   Evidence Luciferase reporter assays comparing methylated and unmethylated PKP3 gene-body sequence

   PMID:34415821

   Open questions at the time

   • Endogenous methylation status across tissues not mapped
   • Transcription factors acting at this element not identified
5. 2023 Low

   Extended the PKP3/MAPK axis to a downstream effector, linking PKP3 to ERCC1 expression and to promoter-methylation-based regulation in ovarian granulosa cells.

   Evidence OE/KD of PKP3 and ERCC1 with Western blot for MAPK, promoter methylation analysis, proliferation/apoptosis assays

   PMID:37420272

   Open questions at the time

   • No direct biochemical reconstitution of the PKP3/MAPK/ERCC1 axis
   • Promoter methylation assessed indirectly
   • Single lab
6. 2024 Low

   Positioned PKP3 within an upstream regulatory cascade, showing FERMT1 acts through PKP3 to activate p38 MAPK and drive lung cancer migration/invasion.

   Evidence FERMT1 overexpression with PKP3 knockdown epistasis, Western blot for p38 MAPK, Transwell assays in NSCLC

   PMID:38200443

   Open questions at the time

   • No direct FERMT1-PKP3 or PKP3-p38 physical interaction shown
   • Epistasis inferred from KD/OE only
   • Single lab
7. 2025 Medium

   Resolved a direct post-transcriptional regulator and a cell-death output, validating PKP3 as a miR-10b-5p target that sustains RIPK3/MLKL necroptosis signaling.

   Evidence Dual luciferase 3'UTR reporter, RIPK3/MLKL Western blot, knockdown rescue, and xenograft model in lung adenocarcinoma

   PMID:40116080

   Open questions at the time

   • Mechanism by which PKP3 sustains RIPK3/MLKL activity not defined
   • Direct physical interaction with necroptosis machinery not shown
   • Single lab

• How PKP3's desmosomal/structural role integrates with its signaling functions in Wnt, MAPK, and necroptosis, and what its direct transcriptional or effector partners are, remains unresolved.
• No direct PKP3 transcriptional targets identified
• No structural model of signaling complexes
• Integration of multiple pathway roles not reconciled in one system