Affinage

FERMT1

Fermitin family homolog 1 · UniProt Q9BQL6

Length
677 aa
Mass
77.4 kDa
Annotated
2026-04-28
36 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FERMT1 (kindlin-1) is a FERM-domain focal adhesion protein that activates β1 integrins in epithelial cells and transduces integrin-dependent signals into multiple downstream pathways controlling cell adhesion, migration, epithelial-mesenchymal transition (EMT), DNA damage repair, and ferroptosis suppression. FERMT1 directly binds β-catenin to stabilize it and promote Wnt/TCF-dependent transcription, and independently engages EGFR to activate AKT and ERK signaling, while also facilitating MIB1-mediated proteasomal degradation of CK1α downstream of ITGB1 mechanotransduction to amplify Wnt signaling (PMID:27641329, PMID:39353234, PMID:40044983). Loss of FERMT1 in keratinocytes causes Kindler syndrome, characterized by integrin activation failure, skin fragility, impaired UV-induced DNA repair, and paracrine cytokine-driven dermal fibrosis (PMID:19762710, PMID:21309038, PMID:27725201). FERMT1 additionally suppresses ferroptosis through interaction with the lysophospholipid acyltransferase MBOAT2 and is transcriptionally regulated by CARM1-mediated H3R17me2 histone methylation and by miR-24-directed mRNA silencing (PMID:41093166, PMID:40016178, PMID:31165706).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2009 High

    The fundamental question of whether FERMT1 directly participates in integrin activation was resolved: overexpression restored active β1 integrin levels in Kindler syndrome keratinocytes, establishing FERMT1 as a bona fide integrin activator at focal adhesions.

    Evidence Loss-of-function patient keratinocytes with overexpression rescue and integrin activation assays

    PMID:19762710

    Open questions at the time
    • Structural basis of FERMT1–integrin tail interaction not defined
    • Relative contribution versus kindlin-2 in same cell type unknown
  2. 2011 Medium

    It was unknown how FERMT1 loss in epidermis leads to progressive dermal fibrosis in Kindler syndrome; this study showed that kindlin-1-deficient keratinocytes secrete paracrine cytokines (IL-20, IL-24, TGF-β2, PDGFB, CTGF) that activate fibroblasts, revealing a non-cell-autonomous fibrotic mechanism.

    Evidence siRNA knockdown in keratinocytes, cytokine profiling, and co-culture with dermal fibroblasts

    PMID:21309038

    Open questions at the time
    • Which cytokine(s) are necessary and sufficient not individually tested
    • In vivo validation in conditional knockout model absent
  3. 2014 Medium

    The regulatory architecture of FERMT1 transcription was clarified when promoter mutations (including c.-20A>G) in Kindler syndrome patients were shown to abolish transcription, defining critical cis-regulatory elements.

    Evidence Luciferase reporter assay and RT-PCR in patient keratinocytes

    PMID:25156791

    Open questions at the time
    • Transcription factor(s) binding the affected promoter elements not identified in this study
    • Genotype–phenotype correlation with different promoter variants not established
  4. 2016 High

    FERMT1's signaling repertoire was extended beyond integrins: direct binding to β-catenin was demonstrated, and FERMT1 was shown to stabilize β-catenin, promote its nuclear translocation, and activate Wnt/TCF transcription to drive EMT, establishing a mechanistic link to canonical Wnt signaling.

    Evidence Co-IP, nuclear fractionation, TCF/LEF luciferase reporter, pharmacological epistasis with Wnt activator/inhibitor, xenograft models in colon cancer cells

    PMID:27641329

    Open questions at the time
    • Domain on FERMT1 mediating β-catenin interaction not mapped
    • Whether this mechanism operates in normal epithelium versus only cancer cells unclear
  5. 2016 Medium

    The role of FERMT1 in genome maintenance was uncovered: kindlin-1-deficient keratinocytes showed impaired DNA repair after UV, with increased γH2AX and cyclobutane pyrimidine dimers, linking FERMT1 loss to NF-κB/JNK hyperactivation and apoptosis, and revealing JunB-dependent transcriptional regulation of FERMT1.

    Evidence siRNA knockdown, UV irradiation, γH2AX/CPD immunofluorescence, pharmacological JNK/NF-κB inhibition, ChIP for JunB at FERMT1 promoter

    PMID:27725201

    Open questions at the time
    • Direct versus indirect role of FERMT1 in DNA repair machinery not delineated
    • Whether DNA repair defect contributes to Kindler syndrome cancer risk not tested
  6. 2019 Medium

    Post-transcriptional regulation of FERMT1 was established when miR-24 was shown to directly target the FERMT1 3′-UTR, and FERMT1 re-expression rescued the growth suppression and radiosensitization caused by miR-24.

    Evidence Luciferase 3′-UTR reporter assay, miRNA overexpression, lentiviral FERMT1 rescue in esophageal cancer cells

    PMID:31165706

    Open questions at the time
    • Physiological contexts in which miR-24–FERMT1 axis operates beyond cancer unknown
    • Other miRNAs targeting FERMT1 not surveyed
  7. 2024 Medium

    A direct FERMT1–EGFR interaction was demonstrated, showing that FERMT1 activates both EGFR/AKT/β-catenin and EGFR/ERK axes to drive EMT and metastasis, thus broadening FERMT1's role from integrin co-activator to receptor tyrosine kinase signaling scaffold.

    Evidence Co-IP, immunofluorescence co-localization, pathway inhibitor rescue, xenograft and lung metastasis models in hepatocellular carcinoma

    PMID:39353234

    Open questions at the time
    • Binding domain on EGFR and FERMT1 not mapped
    • Whether FERMT1 affects EGFR internalization or surface stability not tested
  8. 2025 Medium

    FERMT1 was placed within a mechanotransduction–Wnt axis: under ECM stiffness, FERMT1 acts downstream of ITGB1 to recruit E3 ligase MIB1 for proteasomal degradation of CK1α, thereby activating Wnt signaling and cancer stemness, providing an integrin-to-Wnt mechanistic link.

    Evidence Co-IP, ubiquitination assay, proteasome inhibitor treatment, stiffness-controlled ECM, in vivo OSCC model

    PMID:40044983

    Open questions at the time
    • Whether FERMT1 directly binds MIB1 or CK1α individually not resolved
    • Generalizability beyond oral squamous cell carcinoma not tested
  9. 2025 Medium

    An unexpected anti-ferroptotic function was uncovered: FERMT1 interacts with lysophospholipid acyltransferase MBOAT2 to suppress ferroptosis, with full epistasis confirming MBOAT2 as the effector.

    Evidence Co-IP, erastin-induced ferroptosis assay, MBOAT2 epistasis (double manipulation), glioma cells

    PMID:41093166

    Open questions at the time
    • Lipid species remodeled by FERMT1–MBOAT2 interaction not profiled
    • Structural basis of FERMT1–MBOAT2 interaction unknown
  10. 2025 Medium

    Epigenetic control of FERMT1 was defined: CARM1 deposits H3R17me2 at the FERMT1 promoter to activate transcription, with CARM1 itself stabilized by PSMD14-mediated deubiquitination, revealing a PSMD14–CARM1–FERMT1 regulatory axis.

    Evidence ChIP for H3R17me2, CARM1 siRNA/overexpression, PSMD14 Co-IP/ubiquitination assay, CARM1 inhibitor SGC2085 in HCC cells

    PMID:40016178

    Open questions at the time
    • Whether CARM1–FERMT1 regulation operates in normal epithelial tissues not assessed
    • Other epigenetic marks at the FERMT1 locus not surveyed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for FERMT1's multi-partner interactions (β-catenin, EGFR, MBOAT2, MIB1), how FERMT1 coordinates integrin activation with its non-integrin signaling functions in normal versus transformed cells, and whether the DNA repair function is direct or secondary to adhesion signaling defects.
  • No crystal structure or cryo-EM of FERMT1 in complex with any non-integrin partner
  • Conditional knockout mouse studies dissecting individual signaling arms lacking
  • Quantitative separation of integrin-dependent versus integrin-independent FERMT1 functions not achieved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 1
Partners
CSNK1A1CTNNB1EGFRITGB1MBOAT2MIB1PKP3

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Fermitin family homolog-1 (kindlin-1/FERMT1) is required for integrin activation; overexpression of FERMT1 restored active β1 integrin levels and partially rescued the Kindler syndrome cellular phenotype in keratinocytes, demonstrating a direct role in integrin activation at focal adhesions. Loss-of-function (Kindler syndrome patient keratinocytes), overexpression rescue, immunofluorescence, integrin activation assays The American journal of pathology High 19762710
2011 Kindlin-1 (FERMT1) is involved in integrin β1 activation as a phosphoprotein in keratinocytes; loss of kindlin-1 in epidermal keratinocytes leads to paracrine cytokine secretion (IL-20, IL-24, TGF-β2, PDGFB, CTGF) that induces dermal fibroblast activation and myofibroblast differentiation, explaining progressive dermal fibrosis in Kindler syndrome. siRNA knockdown in keratinocytes, cytokine profiling, co-culture experiments, Western blotting Human mutation Medium 21309038
2016 FERMT1 directly interacts with β-catenin (Co-IP), decreases phosphorylation of β-catenin, enhances its nuclear translocation, and increases β-catenin/TCF/LEF transcriptional activity to promote EMT and metastasis in colon cancer cells. Pathway rescue with CHIR99021 (Wnt activator) reversed FERMT1 knockdown effects, and XAV939 (Wnt inhibitor) impaired FERMT1 overexpression effects. Co-immunoprecipitation, phosphorylation assay, nuclear fractionation, luciferase reporter assay, pharmacological epistasis, in vitro migration/invasion assays, in vivo xenograft Oncogene High 27641329
2016 Loss of KIND1 sensitizes keratinocytes to UV-induced NF-κB and JNK activation, impairs DNA repair (increased γH2AX and cyclobutane pyrimidine dimers), reduces cyclin B1, and increases apoptosis; JNK/NF-κB inhibition reduced DNA damage. KIND1 is transcriptionally regulated by JunB. siRNA knockdown, skin graft model in mice, UV irradiation, γH2AX and CPD immunofluorescence, pharmacological JNK/NF-κB inhibition, ChIP/promoter analysis for JunB regulation The Journal of investigative dermatology Medium 27725201
2021 FERMT1 is localized to membrane-associated regions in villous cytotrophoblast and proximal/distal column trophoblast cells; siRNA-mediated depletion of FERMT1 in HTR8-SVneo cells significantly decreased invasion without markedly altering substrate adhesion, implicating FERMT1 in integrin-mediated trophoblast invasion. Immunofluorescence localization, siRNA knockdown, invasion assay (Matrigel transwell), adhesion assay Histochemistry and cell biology Medium 33683437
2019 miR-24 suppresses FERMT1 expression by directly binding the 3'-UTR of FERMT1 mRNA (luciferase assay), and re-expression of FERMT1 reverses the growth suppression and radiosensitization caused by miR-24 overexpression in esophageal cancer cells. Luciferase 3'-UTR reporter assay, miRNA overexpression, lentiviral FERMT1 overexpression, proliferation and radiation resistance assays Journal of biomedical nanotechnology Medium 31165706
2025 FERMT1 acts as an intracellular mechanotransduction effector downstream of ITGB1; FERMT1 promotes proteasomal degradation of CK1α via E3 ubiquitin ligase MIB1, thereby activating the Wnt signaling pathway to drive cancer stem cell characteristics in oral squamous cell carcinoma under ECM stiffness stimulation. Co-IP, ubiquitination assay, proteasome inhibitor treatment, siRNA knockdown, stiffness-controlled ECM experiments, Western blotting, in vivo tumor model Oncogene Medium 40044983
2024 FERMT1 directly interacts with EGFR (confirmed by Co-IP and immunofluorescence co-localization) and activates both EGFR/AKT/β-catenin and EGFR/ERK signaling pathways to promote EMT and metastasis in hepatocellular carcinoma. Co-immunoprecipitation, immunofluorescence double staining, siRNA knockdown, Western blotting, pathway inhibitor rescue, in vivo xenograft and lung metastasis models Translational oncology Medium 39353234
2024 FERMT1 promotes migration and invasion of non-small cell lung cancer by upregulating PKP3 expression, which in turn activates the p38 MAPK signaling pathway; PKP3 knockdown abolishes the p38 MAPK activation induced by FERMT1 overexpression. siRNA knockdown, Western blotting, Transwell migration/invasion assays, epistasis by PKP3 knockdown BMC cancer Medium 38200443
2025 FERMT1 interacts with MBOAT2 (lysophospholipid acyltransferase) to suppress ferroptosis in glioma cells; MBOAT2 depletion abolishes the anti-ferroptotic effect of FERMT1 overexpression, and MBOAT2 overexpression rescues ferroptosis sensitivity in FERMT1-deficient cells. Co-immunoprecipitation, gain and loss-of-function experiments, erastin-induced ferroptosis assay, ferrostatin-1 rescue, MBOAT2 epistasis Experimental cell research Medium 41093166
2025 CARM1 activates FERMT1 transcription through dimethylation of arginine 17 on histone H3 (H3R17me2); PSMD14-mediated deubiquitination stabilizes CARM1, and CARM1 inhibition with SGC2085 suppresses FERMT1-dependent HCC cell behaviors. ChIP for H3R17me2, siRNA/overexpression of CARM1, PSMD14 co-IP/ubiquitination assays, CARM1 inhibitor (SGC2085), in vitro and in vivo functional assays Cell death & disease Medium 40016178
2022 FERMT1 knockdown inhibits EMT and cell migration in nasopharyngeal carcinoma by directly binding NLRP3 (confirmed by Co-IP) and inhibiting the NF-κB signaling pathway. Co-immunoprecipitation, siRNA knockdown, Western blotting, Transwell assay, xenograft model Cancer cell international Low 35144617
2024 FERMT1 knockdown inhibits EMT and migration of human nasal epithelial cells via inactivation of the PI3K/Akt signaling pathway; Akt inhibitor partially blocked EMT induced by FERMT1 overexpression, establishing epistasis. siRNA knockdown, FERMT1 overexpression, RNA sequencing, PI3K/Akt inhibitor treatment, mouse CRSwNP model International immunopharmacology Low 39488921
2014 Mutations in the FERMT1 promoter region (including a c.-20A>G SNV and large deletions) abolish FERMT1 gene transcription, as demonstrated by reporter assays and absence of mRNA/protein in patient keratinocytes. Luciferase reporter assay, RT-PCR/mRNA expression analysis in patient skin, deletion mapping Clinical genetics Medium 25156791

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 FERMT1 mediates epithelial-mesenchymal transition to promote colon cancer metastasis via modulation of β-catenin transcriptional activity. Oncogene 94 27641329
2011 Kindler syndrome: extension of FERMT1 mutational spectrum and natural history. Human mutation 90 21936020
2003 URP1: a member of a novel family of PH and FERM domain-containing membrane-associated proteins is significantly over-expressed in lung and colon carcinomas. Biochimica et biophysica acta 65 12697302
2006 Molecular basis of Kindler syndrome in Italy: novel and recurrent Alu/Alu recombination, splice site, nonsense, and frameshift mutations in the KIND1 gene. The Journal of investigative dermatology 52 16675959
2006 Novel KIND1 gene mutation in Kindler syndrome with severe gastrointestinal tract involvement. Archives of dermatology 42 17178989
2015 Comparative distribution and in vitro activities of the urotensin II-related peptides URP1 and URP2 in zebrafish: evidence for their colocalization in spinal cerebrospinal fluid-contacting neurons. PloS one 39 25781313
2009 Loss-of-function FERMT1 mutations in kindler syndrome implicate a role for fermitin family homolog-1 in integrin activation. The American journal of pathology 36 19762710
2011 Induction of phenotype modifying cytokines by FERMT1 mutations. Human mutation 28 21309038
2011 Novel and recurrent FERMT1 gene mutations in Kindler syndrome. Acta dermato-venereologica 24 21336475
2022 FERMT1 contributes to the migration and invasion of nasopharyngeal carcinoma through epithelial-mesenchymal transition and cell cycle arrest. Cancer cell international 20 35144617
2022 Urotensin II-related peptides, Urp1 and Urp2, control zebrafish spine morphology. eLife 20 36453722
2021 FERMT1 knockdown inhibits oral squamous cell carcinoma cell epithelial-mesenchymal transition by inactivating the PI3K/AKT signaling pathway. BMC oral health 19 34814915
2019 The Effect of FERMT1 Regulated by miR-24 on the Growth and Radiation Resistance of Esophageal Cancer. Journal of biomedical nanotechnology 15 31165706
2014 FERMT1 promoter mutations in patients with Kindler syndrome. Clinical genetics 15 25156791
2014 New intragenic and promoter region deletion mutations in FERMT1 underscore genetic homogeneity in Kindler syndrome. Clinical and experimental dermatology 14 24635080
2005 An Indian child with Kindler syndrome resulting from a new homozygous nonsense mutation (C468X) in the KIND1 gene. Clinical and experimental dermatology 13 15807691
2011 Evaluating differentiation propensity of in-house derived human embryonic stem cell lines KIND-1 and KIND-2. In vitro cellular & developmental biology. Animal 11 21614653
2024 FERMT1 promotes cell migration and invasion in non-small cell lung cancer via regulating PKP3-mediated activation of p38 MAPK signaling. BMC cancer 10 38200443
2016 KIND1 Loss Sensitizes Keratinocytes to UV-Induced Inflammatory Response and DNA Damage. The Journal of investigative dermatology 8 27725201
2025 PSMD14-mediated deubiquitination of CARM1 facilitates the proliferation and metastasis of hepatocellular carcinoma by inducing the transcriptional activation of FERMT1. Cell death & disease 7 40016178
2022 Identification of FERMT1 and SGCD as key marker in acute aortic dissection from the perspective of predictive, preventive, and personalized medicine. The EPMA journal 7 36505894
2020 A novel frameshift mutation in the FERMT1 gene in a Chinese patient with Kindler syndrome. Experimental and therapeutic medicine 5 32973952
2015 A novel large deletion mutation of FERMT1 gene in a Chinese patient with Kindler syndrome. Journal of Zhejiang University. Science. B 5 26537214
2024 FERMT1 promotes epithelial-mesenchymal transition of hepatocellular carcinoma by activating EGFR/AKT/β-catenin and EGFR/ERK pathways. Translational oncology 4 39353234
1993 Yeast single copy gene URP1 is a homolog of rat ribosomal protein gene L21. Current genetics 4 8428379
2025 ITGB1/FERMT1 mechanoactivation enhances CD44 characteristic stemness in oral squamous cell carcinoma via ubiquitin-dependent CK1α degradation. Oncogene 3 40044983
2024 FERMT1 suppression induces anti-tumor effects and reduces stemness in glioma cancer cells. Journal of cancer research and clinical oncology 3 38976072
2021 Examination of FERMT1 expression in placental chorionic villi and its role in HTR8-SVneo cell invasion. Histochemistry and cell biology 3 33683437
2024 Identification of a novel FERMT1 variant causing kindler syndrome and a review of the clinical and molecular genetic features in Chinese patients. Frontiers in pediatrics 2 39309641
2020 A novel pathogenic FERMT1 variant in four families with Kindler syndrome in Argentina. Pediatric dermatology 2 31957900
2025 FERMT1 suppresses the ferroptosis of glioma cells by interacting with MBOAT2. Experimental cell research 1 41093166
2024 FERMT1 contributes to the epithelial-mesenchymal transition of chronic rhinosinusitis with nasal polyps via PI3K/Akt signaling. International immunopharmacology 1 39488921
2026 Multi-omics analysis links FERMT1 expression to patient survival, immunotherapy response, and metastasis across cancers. Translational cancer research 0 41674941
2025 A Novel Homozygous 9385 bp Deletion in the FERMT1 (KIND1) Gene in a Malaysian Family with Kindler Epidermolysis bullosa and a Review of Large Deletions. International journal of molecular sciences 0 40362475
2017 Evaluating KIND1 human embryonic stem cell-derived pancreatic progenitors to ameliorate streptozotocin-induced diabetes in mice. The Indian journal of medical research 0 29265026
2016 A Novel Nonsense Mutation in Exon 5 of KIND1 Gene in an Iranian Family with Kindler Syndrome. Archives of Iranian medicine 0 27293055