Affinage

FERMT1

Fermitin family homolog 1 · UniProt Q9BQL6

Length
677 aa
Mass
77.4 kDa
Annotated
2026-06-09
36 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FERMT1 (kindlin-1) is a membrane-associated FERM/PH domain protein that activates β1 integrin in epithelial cells and couples the extracellular matrix to cytoskeletal and signaling machinery (PMID:12697302, PMID:19762710). In keratinocytes it is required for active β1 integrin and the integrity of hemidesmosomal components including β4 integrin, laminin-332, and collagens IV/VII/XVII; loss-of-function impairs this anchoring program and causes Kindler syndrome, additionally triggering paracrine cytokine release that drives dermal fibrosis and sensitizing cells to UV-induced DNA damage and NF-κB/JNK inflammatory signaling (PMID:19762710, PMID:21309038, PMID:27725201). Beyond adhesion, FERMT1 acts as an intracellular mechanotransduction effector downstream of stiffness-activated ITGB1, where it directs MIB1-mediated proteasomal degradation of CK1α to activate Wnt signaling and promote CD44+ cancer stem cell properties (PMID:40044983). FERMT1 directly binds β-catenin to reduce its phosphorylation and enhance nuclear β-catenin/TCF/LEF transcription (PMID:27641329), and engages EGFR to activate AKT/β-catenin and ERK cascades (PMID:39353234), collectively driving EMT, migration, and invasion across colon, hepatocellular, oral, lung, and nasopharyngeal cancers (PMID:27641329, PMID:34814915, PMID:38200443, PMID:39353234). FERMT1 also physically interacts with MBOAT2 to suppress ferroptosis in glioma (PMID:41093166). Its expression is controlled upstream by CARM1-mediated H3R17 dimethylation at the FERMT1 locus and by miR-24 binding to the 3'-UTR (PMID:40016178, PMID:31165706).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 Medium

    Established the molecular architecture of FERMT1, defining it as a membrane-associated FERM/PH domain protein and predicting a cytoskeleton-to-membrane linker and signaling role.

    Evidence Cloning, sequence homology, Northern blot, and genomic structure analysis

    PMID:12697302

    Open questions at the time
    • No functional partner or substrate identified
    • Expression reported as restricted to neuromuscular tissue, leaving its epithelial role unaddressed
  2. 2009 High

    Defined FERMT1 as a keratinocyte integrin activator, mechanistically linking its loss to the hemidesmosomal and laminin defects of Kindler syndrome.

    Evidence Integrin activation assays, immunofluorescence, and overexpression rescue in patient keratinocytes

    PMID:19762710

    Open questions at the time
    • Direct biochemical mechanism of β1 integrin activation not resolved
    • Does not address non-adhesion signaling roles
  3. 2011 Medium

    Showed FERMT1 deficiency acts non-cell-autonomously, releasing paracrine cytokines that drive fibroblast-to-myofibroblast conversion and connective tissue remodeling.

    Evidence siRNA knockdown, expression profiling, cytokine assays, and fibroblast co-culture

    PMID:21309038

    Open questions at the time
    • Causal link between integrin loss and cytokine upregulation not mechanistically traced
    • In vivo relevance to Kindler skin fibrosis not established
  4. 2016 High

    Identified a direct FERMT1–β-catenin interaction that stabilizes β-catenin and activates Wnt/TCF/LEF transcription, recasting FERMT1 as a transcriptional driver of EMT and metastasis.

    Evidence Co-IP, TCF/LEF reporter assays, nuclear fractionation, and pharmacological Wnt modulation in colon cancer

    PMID:27641329

    Open questions at the time
    • Domain mediating β-catenin binding not mapped
    • Relationship to FERMT1's integrin role unclear
  5. 2016 Medium

    Connected FERMT1 loss to UV photosensitivity, showing it restrains NF-κB/JNK inflammatory signaling and supports DNA repair and proliferation, and is itself a JunB transcriptional target.

    Evidence siRNA, γH2AX/CPD immunofluorescence, JNK/NF-κB inhibition, and mouse skin grafts

    PMID:27725201

    Open questions at the time
    • Mechanism linking FERMT1 to DNA repair not defined
    • Direct vs indirect control of NF-κB/JNK unresolved
  6. 2019 Medium

    Placed FERMT1 downstream of miR-24, establishing post-transcriptional control of its levels that governs cancer cell growth and radiosensitivity.

    Evidence 3'-UTR luciferase assay, miRNA/overexpression rescue, and xenografts in esophageal cancer

    PMID:31165706

    Open questions at the time
    • Downstream effectors of FERMT1 in radioresistance not identified
    • Single-lab finding
  7. 2021 Medium

    Extended FERMT1's pro-invasive role to trophoblast and to PI3K/AKT-dependent EMT in oral carcinoma, broadening its tissue context beyond keratinocytes.

    Evidence Immunofluorescence localization, siRNA, invasion assays, and PI3K/AKT pharmacological rescue

    PMID:33683437 PMID:34814915

    Open questions at the time
    • Direct molecular targets in PI3K/AKT activation not shown
    • Adhesion-independent mechanism of trophoblast invasion unexplained
  8. 2022 Low

    Proposed a FERMT1–NLRP3 interaction linking FERMT1 to NF-κB-driven EMT in nasopharyngeal carcinoma.

    Evidence Single Co-IP, siRNA, western blot, and xenografts

    PMID:35144617

    Open questions at the time
    • Single Co-IP without reciprocal validation
    • Pathway placement rests on western blot only
  9. 2024 Medium

    Identified FERMT1–EGFR coupling that activates AKT/β-catenin and ERK cascades, and a PKP3/p38 MAPK axis, integrating FERMT1 into receptor tyrosine kinase signaling in cancer.

    Evidence Co-IP, co-localization, pharmacological EGFR/AKT/ERK inhibition, and PKP3 knockdown rescue in HCC and NSCLC

    PMID:38200443 PMID:39353234

    Open questions at the time
    • PKP3 regulation by FERMT1 lacks direct binding evidence
    • Whether EGFR and β-catenin pathways converge mechanistically unclear
  10. 2025 Medium

    Revealed FERMT1 as a stiffness-sensing ITGB1 effector that degrades CK1α via MIB1 to activate Wnt and confer cancer stem cell traits, and as an MBOAT2-binding suppressor of ferroptosis.

    Evidence ECM stiffness assays, ubiquitination assays, Co-IP, and ferroptosis gain/loss experiments in oral carcinoma and glioma

    PMID:40044983 PMID:41093166

    Open questions at the time
    • Structural basis of MIB1 and MBOAT2 engagement unknown
    • How mechanical input is transduced to FERMT1 not defined
  11. 2025 Medium

    Defined upstream epigenetic control, showing CARM1-mediated H3R17me2 transcriptionally activates FERMT1, with PSMD14 stabilizing CARM1.

    Evidence ChIP for H3R17me2 at the FERMT1 locus, Co-IP, and CARM1 inhibitor (SGC2085) in HCC

    PMID:40016178

    Open questions at the time
    • Whether CARM1 directly occupies the FERMT1 promoter vs broad chromatin effect not resolved
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FERMT1's canonical integrin-adhesion function mechanistically connects to its diverse cancer signaling roles (Wnt, EGFR, ferroptosis) remains unresolved.
  • No structural model linking FERM/PH domains to β-catenin, EGFR, NLRP3, or MBOAT2 binding
  • Whether adhesion and oncogenic signaling are coupled or independent functions is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0008092 cytoskeletal protein binding 1 GO:0060089 molecular transducer activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-1643685 Disease 2 R-HSA-5357801 Programmed Cell Death 1
Partners
CTNNB1EGFRITGB1MBOAT2MIB1NLRP3

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 FERMT1 (URP1) encodes a membrane-associated protein containing both FERM and PH domains, with normal expression restricted to neuromuscular tissues; the FERM domain is related to cytoplasmic plasma membrane-to-cytoskeleton linkers and the PH domain is typical of membrane-anchored signal transduction proteins. Cloning, sequence homology analysis, Northern blot, genomic structure analysis Biochimica et biophysica acta Medium 12697302
2009 Fermitin family homolog-1 (kindlin-1/FERMT1) is required for integrin activation in keratinocytes: overexpression of FERMT1 restored active β1 integrin levels and partially rescued the Kindler syndrome cellular phenotype (loss of β4 integrin localization, random laminin-332 distribution), while loss-of-function mutations led to reduced active β1 integrin and disruption of hemidesmosomal components including β4 integrin, types IV/VII/XVII collagens, and laminin-332. Immunofluorescence, integrin activation assay, overexpression rescue experiment in Kindler syndrome keratinocytes The American journal of pathology High 19762710
2011 Kindlin-1 (FERMT1) is an epithelial-specific phosphoprotein involved in integrin β1 activation; loss of kindlin-1 in keratinocytes causes upregulation of paracrine cytokines (IL-20, IL-24, TGF-β2, IL1F5, PDGFB, CTGF) that drive dermal inflammation and fibroblast differentiation to myofibroblasts, revealing an indirect pathway from intracellular FERMT1 deficiency to connective tissue remodeling. siRNA knockdown, gene expression profiling, cytokine secretion assays, co-culture experiments with fibroblasts Human mutation Medium 21309038
2016 FERMT1 directly interacts with β-catenin and activates the Wnt/β-catenin signaling pathway by decreasing phosphorylation of β-catenin, enhancing its nuclear translocation, and increasing β-catenin/TCF/LEF transcriptional activity, thereby promoting EMT and colon cancer metastasis. Co-immunoprecipitation, reporter assays (β-catenin/TCF/LEF transcription), phosphorylation assays, nuclear fractionation, rescue experiments with CHIR99021 (Wnt activator) and XAV939 (Wnt inhibitor), in vitro and in vivo migration/invasion assays Oncogene High 27641329
2016 KIND1/FERMT1 loss sensitizes keratinocytes to UV-induced inflammatory signaling via NF-κB and c-Jun N-terminal kinase (JNK) activation, impairs DNA repair (increased γH2AX and cyclobutane pyrimidine dimers persisting 24 h post-UVB), and reduces cyclinB1-dependent proliferation; pharmacological or genetic JNK/NF-κB inhibition reduced DNA damage markers. Additionally, KIND1 transcription is regulated by JunB. Gene silencing (siRNA), immunofluorescence for γH2AX and cyclobutane pyrimidine dimers, western blot, JNK/NF-κB pharmacological inhibition, skin graft regeneration assay in mice, promoter/transcription factor analysis The Journal of investigative dermatology Medium 27725201
2019 miR-24 directly binds to the 3'-UTR of FERMT1 mRNA and suppresses FERMT1 expression; forced miR-24 expression suppressed esophageal cancer cell growth and enhanced radiosensitivity, effects that were reversed by re-expression of FERMT1, placing FERMT1 downstream of miR-24 in a regulatory axis controlling radiation resistance. Luciferase reporter assay (3'-UTR binding), lentiviral overexpression, siRNA/miRNA transfection, proliferation assay, radiosensitivity assay, in vivo xenograft Journal of biomedical nanotechnology Medium 31165706
2021 FERMT1 is expressed at membrane-associated regions of villous cytotrophoblast and distal cell column trophoblast cells; siRNA-mediated depletion of FERMT1 in HTR8-SVneo trophoblast cells significantly decreased invasion (but did not markedly alter cell-substrate adhesion), demonstrating a role for FERMT1 in trophoblast invasion. Immunofluorescence localization in placental tissue, siRNA knockdown, Matrigel invasion assay, adhesion assay Histochemistry and cell biology Medium 33683437
2021 FERMT1 knockdown inhibits EMT in oral squamous cell carcinoma via inactivation of the PI3K/AKT signaling pathway; pharmacological activation of PI3K/AKT reversed the effect of FERMT1 silencing on migration, invasion, and EMT markers. siRNA knockdown, western blot, RT-qPCR, Transwell assay, PI3K/AKT pathway pharmacological rescue experiments BMC oral health Medium 34814915
2022 FERMT1 directly interacts with NLRP3 (Nod-like receptor family protein 3) and knockdown of FERMT1 inhibits EMT through this interaction and inhibition of the NF-κB signaling pathway in nasopharyngeal carcinoma cells. Co-immunoprecipitation, siRNA knockdown, western blot, wound healing assay, Transwell assay, flow cytometry, in vivo xenograft Cancer cell international Low 35144617
2024 FERMT1 promotes cell migration and invasion in non-small cell lung cancer by upregulating PKP3 (plakophilin 3), which in turn activates the p38 MAPK signaling pathway; PKP3 knockdown counteracted p38 MAPK activation induced by FERMT1 overexpression. Western blot, Transwell migration/invasion assay, siRNA knockdown, pathway inhibitor experiments BMC cancer Low 38200443
2024 FERMT1 directly interacts with EGFR and activates the EGFR/AKT/β-catenin and EGFR/ERK signaling pathways to promote EMT, invasion, and migration in hepatocellular carcinoma; inhibition of EGFR, AKT, or ERK confirmed pathway dependence. Co-immunoprecipitation, immunofluorescence double staining, siRNA knockdown, western blot, pharmacological inhibitors of EGFR/AKT/ERK, Transwell assay, in vivo mouse models Translational oncology Medium 39353234
2025 FERMT1 suppresses ferroptosis in glioma cells by physically interacting with MBOAT2; FERMT1 overexpression protected cells from erastin-induced ferroptosis, FERMT1 deficiency sensitized cells, depletion of MBOAT2 abolished FERMT1's anti-ferroptotic effects, and MBOAT2 overexpression rescued ferroptosis in FERMT1-deficient cells. Co-immunoprecipitation (FERMT1-MBOAT2 interaction), gain- and loss-of-function experiments, erastin-induced ferroptosis assay, ferrostatin-1 rescue experiment Experimental cell research Medium 41093166
2025 ECM mechanical stiffening activates ITGB1, which signals through FERMT1 as an intracellular mechanotransduction effector; FERMT1 promotes proteasomal degradation of CK1α via E3 ubiquitin ligase MIB1, thereby activating the Wnt signaling pathway and driving CD44+ cancer stem cell characteristics in oral squamous cell carcinoma. Mechanobiology assays (ECM stiffness manipulation), siRNA/overexpression experiments, co-immunoprecipitation, ubiquitination assay, western blot, in vivo tumor models Oncogene Medium 40044983
2025 CARM1 transcriptionally activates FERMT1 through dimethylation of arginine 17 on histone H3 (H3R17me2); PSMD14-mediated deubiquitination stabilizes CARM1, and CARM1 inhibition with SGC2085 suppresses FERMT1 expression and HCC cell malignant behaviors. ChIP assay (H3R17me2 at FERMT1 locus), co-immunoprecipitation, western blot, gain/loss-of-function, pharmacological CARM1 inhibitor (SGC2085), in vitro and in vivo experiments Cell death & disease Medium 40016178

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 95 27641329
2011 Kindler syndrome: extension of FERMT1 mutational spectrum and natural history. Human mutation 91 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 66 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 41 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 37 19762710
2011 Induction of phenotype modifying cytokines by FERMT1 mutations. Human mutation 29 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 21 35144617
2022 Urotensin II-related peptides, Urp1 and Urp2, control zebrafish spine morphology. eLife 21 36453722
2021 FERMT1 knockdown inhibits oral squamous cell carcinoma cell epithelial-mesenchymal transition by inactivating the PI3K/AKT signaling pathway. BMC oral health 20 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 9 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
2024 FERMT1 contributes to the epithelial-mesenchymal transition of chronic rhinosinusitis with nasal polyps via PI3K/Akt signaling. International immunopharmacology 2 39488921
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
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

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