KRT18

KRT18 is a type I keratin whose expression and post-transcriptional regulation position it as an effector in epithelial cell adhesion, proliferation, and cell-death signaling (PMID:37620903, PMID:35136989). At the cell surface it directly binds and stabilizes E-cadherin in trophoblast cells, thereby promoting trophoblast migration, invasion, and embryo adhesion/implantation (PMID:37620903). In epithelial cancers KRT18 acts as a growth-promoting node: it activates MAPK/ERK signaling to drive gastric and cholangiocarcinoma cell proliferation, migration, and stemness (PMID:35136989, PMID:39776371), and its knockdown reprograms expression and alternative splicing of apoptosis and cell-cycle genes, promoting apoptosis and inhibiting proliferation (PMID:34290732). In tubular epithelial cells, elevated KRT18 activates the RIPK1/MLKL necroptosis pathway, contributing to diabetic nephropathy progression (PMID:42165125). KRT18 abundance is tightly controlled at multiple levels: transcriptionally via the transcription factor EGR1 (PMID:24990820) and via P300-mediated H3K18 acetylation at its locus (PMID:42165125); through METTL3-dependent m6A modification that stabilizes its mRNA (PMID:35136989); and through negative post-transcriptional repression by miR-186-3p and miR-194-5p (PMID:35258413, PMID:39776371). Host KRT18 additionally serves as an interaction partner for Cryptosporidium parvum protein disulfide isomerase in a non-redox-dependent manner, a binding required for efficient parasite infection (PMID:41275047).

1. 2014 Low

   Established an upstream transcriptional regulator of KRT18, framing it as a controlled gene rather than a constitutive structural protein.

   Evidence Promoter analysis and bioinformatics identifying an EGR1 binding site in the KRT18 promoter in NSCLC

   PMID:24990820

   Open questions at the time

   • Binding identified by bioinformatics/promoter analysis without direct ChIP or reporter validation
   • Functional consequence of EGR1-driven KRT18 not demonstrated
   • Restricted to a single cancer context
2. 2021 Medium

   Showed KRT18 has a regulatory role in gene expression beyond structure, linking it to apoptosis and cell-cycle control.

   Evidence siRNA knockdown plus whole-transcriptome RNA-seq with apoptosis/proliferation validation in gastric cancer AGS cells

   PMID:34290732

   Open questions at the time

   • Mechanism by which KRT18 influences splicing is unknown
   • No direct RNA or spliceosome interaction shown
   • Single cell line
3. 2022 Medium

   Resolved how KRT18 mRNA stability is set and connected it to a growth-driving signaling output.

   Evidence RIP, m6A methylation assays, and rescue experiments linking LINC02253/METTL3-mediated m6A to KRT18 mRNA stabilization and MAPK/ERK activation in gastric cancer

   PMID:35136989

   Open questions at the time

   • m6A reader mediating stabilization not identified
   • Mechanism by which KRT18 activates MAPK/ERK not defined
   • Single lab
4. 2022 Medium

   Identified a direct microRNA brake on KRT18 controlling proliferation and survival.

   Evidence Biotin-miRNA pull-down, dual luciferase reporter, knockdown, and xenograft assays showing miR-186-3p directly targets KRT18 and represses MAPK signaling in colon cancer

   PMID:35258413

   Open questions at the time

   • Step linking KRT18 to MAPK activation not mechanistically resolved
   • Single tumor type
5. 2023 Medium

   Defined a direct protein-protein function for KRT18 at the cell surface, connecting it to adhesion and embryo implantation.

   Evidence Microscale thermophoresis demonstrating direct KRT18-E-cadherin binding, with knockdown and mouse embryo implantation assays

   PMID:37620903

   Open questions at the time

   • Structural basis of KRT18/E-cadherin interaction unresolved
   • Whether stabilization is direct or via cytoskeletal anchoring unclear
   • Single lab
6. 2025 Medium

   Extended a second direct microRNA-KRT18 axis and a lncRNA sponge, reinforcing KRT18 as a MAPK-linked driver of proliferation and stemness.

   Evidence RNA pulldown, RIP, luciferase, rescue, and xenograft assays showing miR-194-5p targets KRT18 and HCG18 sponges miR-194-5p in cholangiocarcinoma

   PMID:39776371

   Open questions at the time

   • Direct mechanism of KRT18-driven MAPK activation still undefined
   • Stemness readout correlative
   • Single lab
7. 2025 Medium

   Revealed a non-canonical role for host KRT18 as a pathogen interaction partner enabling infection.

   Evidence LC-MS/MS and Co-IP identifying KRT18 binding to Cryptosporidium parvum PDI in a non-redox manner, with knockdown impairing infection

   PMID:41275047

   Open questions at the time

   • Binding interface and stoichiometry not mapped
   • How the interaction promotes invasion mechanistically unknown
   • Reciprocal validation limited
8. 2026 Medium

   Linked an epigenetic writer to KRT18 transcription and to a defined cell-death pathway in disease.

   Evidence shRNA/overexpression, C646 inhibitor, and rescue experiments showing P300/H3K18ac drives KRT18, which activates RIPK1/MLKL necroptosis in an STZ diabetic nephropathy mouse model

   PMID:42165125

   Open questions at the time

   • Mechanism by which KRT18 engages RIPK1/MLKL not defined
   • Whether H3K18ac at KRT18 is direct or indirect unresolved
   • Single lab

• The molecular mechanism by which cytoplasmic KRT18 transduces signals to MAPK/ERK and RIPK1/MLKL, and how it modulates alternative splicing, remains unresolved.
• No structural model of KRT18 signaling complexes
• Direct effectors bridging KRT18 to kinase cascades not identified
• Splicing regulatory mechanism uncharacterized