EPPK1

EPPK1 (epiplakin) is a plakin-family cytoskeletal linker that organizes and protects the keratin intermediate filament network, acting as a stress-inducible keratin chaperone (PMID:25617501, PMID:36231039). It binds keratin 8 and keratin 18 through multiple domains, and in its absence keratin aggregates form more readily under phosphatase-inhibitor or in vivo liver-injury stress—a defect rescuable by the chemical chaperone TMAO—establishing a role in disease-induced keratin reorganization (PMID:25617501). Its engagement of the filament network is conditional: EPPK1 is diffuse in resting cells but undergoes a rapid, reversible, Ca2+-dependent switch to a keratin filament-associated state upon ER, oxidative, or UV stress, where it reduces keratin dynamics and stabilizes the network (PMID:36231039). Consistent with a structural/mechanical role, EPPK1 loss in retinal Müller cells lowers traction forces and alters cell size, shape, and filopodia (PMID:36334068). Beyond cytoskeletal organization, EPPK1 is repeatedly implicated as a driver of epithelial proliferation, invasion, and EMT in cancer: it is transcriptionally activated by KLF5 binding its promoter (PMID:33827480) and post-transcriptionally upregulated through METTL3-mediated m6A modification of its mRNA (PMID:38293837), and it functions downstream as an upstream activator of PI3K/AKT signaling (PMID:35238170, PMID:38293837) and of a p38 MAPK/c-Jun/JUP axis that it engages via direct dihydrotestosterone binding in a non-androgen-receptor manner (PMID:37328487). EPPK1 also acts as an RNA-binding protein that binds and stabilizes YAP mRNA to promote tumor cell proliferation, invasion, and immune escape (PMID:41569058), and its CRISPR knockout drives mesenchymal-to-epithelial transition with MYC downregulation and p53 upregulation (PMID:38594604). In tissue contexts, EPPK1 marks pancreatic and hepatic progenitor/regenerating cell populations (PMID:18498355), and its expression is downregulated by IFN-γ in psoriatic epidermis (PMID:40746860).

1. 2008 Medium

   Established EPPK1 as a marker of progenitor and regenerating epithelial cell populations, linking it to tissue renewal before any mechanistic role was known.

   Evidence Immunohistochemistry and lineage-marker co-expression in mouse embryonic/adult pancreas plus pancreatitis and partial pancreatectomy models

   PMID:18498355

   Open questions at the time

   • Marker-only association with no functional perturbation
   • Does not establish whether EPPK1 contributes to progenitor identity or expansion
2. 2011 Low

   Extended the progenitor-marker observation to hepatic oval cells, suggesting a broadly shared role across epithelial regenerative compartments.

   Evidence Immunohistochemistry and lineage-marker co-localization in CDE-diet mouse liver injury

   PMID:21216305

   Open questions at the time

   • Co-localization only, no functional perturbation of EPPK1
   • Single lab, descriptive
3. 2015 High

   Resolved the first molecular function—EPPK1 binds K8/K18 and acts as a chaperone for stress-induced keratin reorganization—answering what EPPK1 does at the cytoskeleton.

   Evidence Eppk1-/- mouse liver injury models, primary hepatocyte phosphatase-inhibitor treatment, K8/K18 binding assays, TMAO rescue

   PMID:25617501

   Open questions at the time

   • Domain-level determinants of keratin binding not mapped to function
   • Chaperone mechanism inferred from TMAO rescue rather than direct biochemistry
4. 2022 High

   Defined the regulatory logic of keratin engagement—a Ca2+-dependent, stress-triggered switch from diffuse to filament-associated state that reduces keratin dynamics.

   Evidence Live-cell imaging of tagged EPPK1/keratin, Ca2+ manipulation, FRAP under ER/oxidative/UV stress in epithelial cells

   PMID:36231039

   Open questions at the time

   • Ca2+ sensor/effector that drives relocalization unidentified
   • Whether the same switch operates in vivo not tested
5. 2022 Medium

   Showed EPPK1 sets the mechanical properties of epithelial cells, generalizing its cytoskeletal role to traction-force generation and morphology.

   Evidence EPPK1 knockout in a human Müller cell line, traction force microscopy, morphometry

   PMID:36334068

   Open questions at the time

   • Link between traction-force change and keratin organization not established
   • No rescue experiment
6. 2021 High

   Identified the first direct upstream transcriptional regulator (KLF5) and placed EPPK1 upstream of p38 in driving proliferation, opening a cancer-signaling role.

   Evidence ChIP and luciferase reporter for KLF5 at the EPPK1 promoter, siRNA epistasis, p38 western blot, proliferation assays in HeLa cells

   PMID:33827480

   Open questions at the time

   • How EPPK1 mechanistically activates p38 not defined
   • Generality across tumor types not addressed at this stage
7. 2022 Medium

   Connected EPPK1 to PI3K/AKT activation as a driver of proliferation, invasion, and EMT in esophageal squamous carcinoma.

   Evidence siRNA knockdown with proliferation/migration/invasion/apoptosis assays and PI3K/AKT and EMT marker western blots in ESCC cells

   PMID:35238170

   Open questions at the time

   • No rescue experiment
   • Mechanism by which EPPK1 engages PI3K/AKT unknown
8. 2023 High

   Revealed an unexpected ligand-sensing function—direct DHT binding by EPPK1 driving a non-androgen-receptor p38/c-Jun/JUP axis in bladder cancer.

   Evidence Biotinylated DHT pull-down, siRNA, p38 inhibitor, ChIP for c-Jun at JUP promoter, xenograft and BBN carcinogenesis models

   PMID:37328487

   Open questions at the time

   • DHT-binding site/structural basis not defined
   • How DHT binding transduces to p38 activation unresolved
9. 2024 High

   Defined a post-transcriptional control layer—METTL3-mediated m6A modification of EPPK1 mRNA—as an upstream driver of EPPK1 expression and PI3K/AKT signaling.

   Evidence MeRIP, RIP, dual-luciferase, siRNA, EPPK1 rescue, xenograft in esophageal cancer cells

   PMID:38293837

   Open questions at the time

   • m6A reader mediating EPPK1 mRNA fate not identified
   • Whether m6A affects stability vs translation not separated
10. 2024 Medium

    Showed EPPK1 loss reprograms transcription toward an epithelial, tumor-suppressive state (MET, MYC down, p53 up), linking it to lung adenocarcinoma and smoke exposure.

    Evidence CRISPR-Cas9 knockout, RNA-seq, western blot, proliferation/invasion assays, cigarette smoke exposure model

    PMID:38594604

    Open questions at the time

    • Direct vs indirect control of MYC/p53 not distinguished
    • Mechanism connecting EPPK1 to transcriptional reprogramming unknown
11. 2026 Medium

    Established a second molecular activity—EPPK1 as an RNA-binding protein that stabilizes YAP mRNA—defining a post-transcriptional oncogenic axis.

    Evidence RIP for EPPK1-YAP mRNA, mRNA stability assay, siRNA, YAP overexpression rescue, xenograft in ovarian cancer

    PMID:41569058

    Open questions at the time

    • RNA-binding determinants within EPPK1 not mapped
    • Breadth of EPPK1's mRNA targets beyond YAP unknown
12. 2025 Medium

    Placed EPPK1 in inflammatory skin homeostasis, identifying IFN-γ as the cytokine that suppresses it in psoriatic epidermis.

    Evidence scRNA-seq of psoriatic vs healthy skin, immunofluorescence, ex vivo IFN-γ treatment of human skin, RNA-seq of Eppk1-/- murine epidermis

    PMID:40746860

    Open questions at the time

    • Mechanism of IFN-γ-mediated EPPK1 repression not defined
    • Functional consequence of EPPK1 loss for the psoriatic phenotype not established

• How EPPK1's keratin-chaperone/cytoskeletal function mechanistically connects to its cancer signaling roles (PI3K/AKT, p38, YAP mRNA stabilization) remains unresolved.
• No unified mechanism linking filament organization to growth-signaling outputs
• Structural basis of DHT binding and RNA binding undefined
• No structural model of the multidomain protein