{"gene":"FERMT1","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2009,"finding":"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.","method":"Loss-of-function (Kindler syndrome patient keratinocytes), overexpression rescue, immunofluorescence, integrin activation assays","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal loss-of-function and gain-of-function with specific integrin activation readout, replicated in patient material","pmids":["19762710"],"is_preprint":false},{"year":2011,"finding":"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.","method":"siRNA knockdown in keratinocytes, cytokine profiling, co-culture experiments, Western blotting","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined paracrine signaling phenotype, single lab with multiple readouts","pmids":["21309038"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, phosphorylation assay, nuclear fractionation, luciferase reporter assay, pharmacological epistasis, in vitro migration/invasion assays, in vivo xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — direct Co-IP with epistasis via pharmacological Wnt modulation, multiple orthogonal methods in one study","pmids":["27641329"],"is_preprint":false},{"year":2016,"finding":"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.","method":"siRNA knockdown, skin graft model in mice, UV irradiation, γH2AX and CPD immunofluorescence, pharmacological JNK/NF-κB inhibition, ChIP/promoter analysis for JunB regulation","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined DNA damage and signaling phenotypes, pharmacological epistasis, single lab","pmids":["27725201"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Immunofluorescence localization, siRNA knockdown, invasion assay (Matrigel transwell), adhesion assay","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct localization with functional consequence via clean KD, single lab","pmids":["33683437"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Luciferase 3'-UTR reporter assay, miRNA overexpression, lentiviral FERMT1 overexpression, proliferation and radiation resistance assays","journal":"Journal of biomedical nanotechnology","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding confirmed by reporter assay plus rescue experiment, single lab","pmids":["31165706"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-IP, ubiquitination assay, proteasome inhibitor treatment, siRNA knockdown, stiffness-controlled ECM experiments, Western blotting, in vivo tumor model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway established by Co-IP, ubiquitination assay, and rescue experiments, single lab with multiple orthogonal methods","pmids":["40044983"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, immunofluorescence double staining, siRNA knockdown, Western blotting, pathway inhibitor rescue, in vivo xenograft and lung metastasis models","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct Co-IP confirmed interaction, pathway validated by inhibitors, single lab","pmids":["39353234"],"is_preprint":false},{"year":2024,"finding":"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.","method":"siRNA knockdown, Western blotting, Transwell migration/invasion assays, epistasis by PKP3 knockdown","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 — epistasis via double KD, multiple assays, single lab","pmids":["38200443"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation, gain and loss-of-function experiments, erastin-induced ferroptosis assay, ferrostatin-1 rescue, MBOAT2 epistasis","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP confirmed interaction plus epistasis by double manipulation, single lab","pmids":["41093166"],"is_preprint":false},{"year":2025,"finding":"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.","method":"ChIP for H3R17me2, siRNA/overexpression of CARM1, PSMD14 co-IP/ubiquitination assays, CARM1 inhibitor (SGC2085), in vitro and in vivo functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-based epigenetic regulation with pharmacological and genetic validation, single lab with multiple methods","pmids":["40016178"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, Western blotting, Transwell assay, xenograft model","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with limited mechanistic follow-up on the FERMT1–NLRP3 interaction, single lab","pmids":["35144617"],"is_preprint":false},{"year":2024,"finding":"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.","method":"siRNA knockdown, FERMT1 overexpression, RNA sequencing, PI3K/Akt inhibitor treatment, mouse CRSwNP model","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 — pharmacological epistasis without direct binding evidence, single lab","pmids":["39488921"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Luciferase reporter assay, RT-PCR/mRNA expression analysis in patient skin, deletion mapping","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — functional reporter assay plus patient tissue validation, single lab","pmids":["25156791"],"is_preprint":false}],"current_model":"FERMT1 (kindlin-1) is a focal adhesion FERM-domain protein that activates β1 integrins in epithelial cells, localizes to focal adhesions and the cell membrane, and mechanistically engages multiple signaling axes: it directly binds and activates β-catenin/Wnt signaling to drive EMT, interacts with EGFR to stimulate AKT and ERK pathways, acts downstream of ITGB1 mechanotransduction to promote CK1α degradation via MIB1 ubiquitin ligase, suppresses ferroptosis through interaction with MBOAT2, and is transcriptionally regulated by CARM1-mediated H3R17me2 histone methylation and by miR-24; loss-of-function causes Kindler syndrome through defective integrin activation, keratinocyte fragility, impaired DNA repair, and paracrine cytokine-driven dermal fibrosis."},"narrative":{"teleology":[{"year":2009,"claim":"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","pmids":["19762710"],"confidence":"High","gaps":["Structural basis of FERMT1–integrin tail interaction not defined","Relative contribution versus kindlin-2 in same cell type unknown"]},{"year":2011,"claim":"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","pmids":["21309038"],"confidence":"Medium","gaps":["Which cytokine(s) are necessary and sufficient not individually tested","In vivo validation in conditional knockout model absent"]},{"year":2014,"claim":"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","pmids":["25156791"],"confidence":"Medium","gaps":["Transcription factor(s) binding the affected promoter elements not identified in this study","Genotype–phenotype correlation with different promoter variants not established"]},{"year":2016,"claim":"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","pmids":["27641329"],"confidence":"High","gaps":["Domain on FERMT1 mediating β-catenin interaction not mapped","Whether this mechanism operates in normal epithelium versus only cancer cells unclear"]},{"year":2016,"claim":"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","pmids":["27725201"],"confidence":"Medium","gaps":["Direct versus indirect role of FERMT1 in DNA repair machinery not delineated","Whether DNA repair defect contributes to Kindler syndrome cancer risk not tested"]},{"year":2019,"claim":"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","pmids":["31165706"],"confidence":"Medium","gaps":["Physiological contexts in which miR-24–FERMT1 axis operates beyond cancer unknown","Other miRNAs targeting FERMT1 not surveyed"]},{"year":2024,"claim":"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","pmids":["39353234"],"confidence":"Medium","gaps":["Binding domain on EGFR and FERMT1 not mapped","Whether FERMT1 affects EGFR internalization or surface stability not tested"]},{"year":2025,"claim":"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","pmids":["40044983"],"confidence":"Medium","gaps":["Whether FERMT1 directly binds MIB1 or CK1α individually not resolved","Generalizability beyond oral squamous cell carcinoma not tested"]},{"year":2025,"claim":"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","pmids":["41093166"],"confidence":"Medium","gaps":["Lipid species remodeled by FERMT1–MBOAT2 interaction not profiled","Structural basis of FERMT1–MBOAT2 interaction unknown"]},{"year":2025,"claim":"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","pmids":["40016178"],"confidence":"Medium","gaps":["Whether CARM1–FERMT1 regulation operates in normal epithelial tissues not assessed","Other epigenetic marks at the FERMT1 locus not surveyed"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,6,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,6,7]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,9]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3]}],"complexes":[],"partners":["ITGB1","CTNNB1","EGFR","MBOAT2","MIB1","CSNK1A1","PKP3"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q9BQL6","full_name":"Fermitin family homolog 1","aliases":["Kindlerin","Kindlin syndrome protein","Kindlin-1","Unc-112-related protein 1"],"length_aa":677,"mass_kda":77.4,"function":"Involved in cell adhesion. Contributes to integrin activation. When coexpressed with talin, potentiates activation of ITGA2B. Required for normal keratinocyte proliferation. Required for normal polarization of basal keratinocytes in skin, and for normal cell shape. Required for normal adhesion of keratinocytes to fibronectin and laminin, and for normal keratinocyte migration to wound sites. May mediate TGF-beta 1 signaling in tumor progression","subcellular_location":"Cytoplasm, cytoskeleton; Cell junction, focal adhesion; Cell projection, ruffle membrane","url":"https://www.uniprot.org/uniprotkb/Q9BQL6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FERMT1","classification":"Not Classified","n_dependent_lines":63,"n_total_lines":1208,"dependency_fraction":0.052152317880794705},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FERMT1","total_profiled":1310},"omim":[{"mim_id":"607901","title":"FERM DOMAIN-CONTAINING KINDLIN 3; FERMT3","url":"https://www.omim.org/entry/607901"},{"mim_id":"607900","title":"FERM DOMAIN-CONTAINING KINDLIN 1; FERMT1","url":"https://www.omim.org/entry/607900"},{"mim_id":"173650","title":"KINDLER SYNDROME; KNDLRS","url":"https://www.omim.org/entry/173650"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":29.9}],"url":"https://www.proteinatlas.org/search/FERMT1"},"hgnc":{"alias_symbol":["FLJ20116","URP1","KIND1","UNC112A"],"prev_symbol":["C20orf42"]},"alphafold":{"accession":"Q9BQL6","domains":[{"cath_id":"3.10.20.90","chopping":"12-93","consensus_level":"high","plddt":90.2533,"start":12,"end":93},{"cath_id":"2.30.29.30","chopping":"372-478","consensus_level":"medium","plddt":86.5055,"start":372,"end":478},{"cath_id":"2.30.29.30","chopping":"569-675","consensus_level":"high","plddt":89.1756,"start":569,"end":675}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BQL6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BQL6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BQL6-F1-predicted_aligned_error_v6.png","plddt_mean":80.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FERMT1","jax_strain_url":"https://www.jax.org/strain/search?query=FERMT1"},"sequence":{"accession":"Q9BQL6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BQL6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BQL6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BQL6"}},"corpus_meta":[{"pmid":"27641329","id":"PMC_27641329","title":"FERMT1 mediates epithelial-mesenchymal transition to promote colon cancer metastasis via modulation of β-catenin transcriptional activity.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/27641329","citation_count":94,"is_preprint":false},{"pmid":"21936020","id":"PMC_21936020","title":"Kindler syndrome: extension of FERMT1 mutational spectrum and natural history.","date":"2011","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/21936020","citation_count":90,"is_preprint":false},{"pmid":"12697302","id":"PMC_12697302","title":"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.","date":"2003","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/12697302","citation_count":65,"is_preprint":false},{"pmid":"16675959","id":"PMC_16675959","title":"Molecular basis of Kindler syndrome in Italy: novel and recurrent Alu/Alu recombination, splice site, nonsense, and frameshift mutations in the KIND1 gene.","date":"2006","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/16675959","citation_count":52,"is_preprint":false},{"pmid":"17178989","id":"PMC_17178989","title":"Novel KIND1 gene mutation in Kindler syndrome with severe gastrointestinal tract involvement.","date":"2006","source":"Archives of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/17178989","citation_count":42,"is_preprint":false},{"pmid":"25781313","id":"PMC_25781313","title":"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.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25781313","citation_count":39,"is_preprint":false},{"pmid":"19762710","id":"PMC_19762710","title":"Loss-of-function FERMT1 mutations in kindler syndrome implicate a role for fermitin family homolog-1 in integrin activation.","date":"2009","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19762710","citation_count":36,"is_preprint":false},{"pmid":"21309038","id":"PMC_21309038","title":"Induction of phenotype modifying cytokines by FERMT1 mutations.","date":"2011","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/21309038","citation_count":28,"is_preprint":false},{"pmid":"21336475","id":"PMC_21336475","title":"Novel and recurrent FERMT1 gene mutations in Kindler syndrome.","date":"2011","source":"Acta dermato-venereologica","url":"https://pubmed.ncbi.nlm.nih.gov/21336475","citation_count":24,"is_preprint":false},{"pmid":"36453722","id":"PMC_36453722","title":"Urotensin II-related peptides, Urp1 and Urp2, control zebrafish spine morphology.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36453722","citation_count":20,"is_preprint":false},{"pmid":"35144617","id":"PMC_35144617","title":"FERMT1 contributes to the migration and invasion of nasopharyngeal carcinoma through epithelial-mesenchymal transition and cell cycle arrest.","date":"2022","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/35144617","citation_count":20,"is_preprint":false},{"pmid":"34814915","id":"PMC_34814915","title":"FERMT1 knockdown inhibits oral squamous cell carcinoma cell epithelial-mesenchymal transition by inactivating the PI3K/AKT signaling pathway.","date":"2021","source":"BMC oral health","url":"https://pubmed.ncbi.nlm.nih.gov/34814915","citation_count":19,"is_preprint":false},{"pmid":"31165706","id":"PMC_31165706","title":"The Effect of FERMT1 Regulated by miR-24 on the Growth and Radiation Resistance of Esophageal Cancer.","date":"2019","source":"Journal of biomedical 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Animal","url":"https://pubmed.ncbi.nlm.nih.gov/21614653","citation_count":11,"is_preprint":false},{"pmid":"38200443","id":"PMC_38200443","title":"FERMT1 promotes cell migration and invasion in non-small cell lung cancer via regulating PKP3-mediated activation of p38 MAPK signaling.","date":"2024","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38200443","citation_count":10,"is_preprint":false},{"pmid":"27725201","id":"PMC_27725201","title":"KIND1 Loss Sensitizes Keratinocytes to UV-Induced Inflammatory Response and DNA Damage.","date":"2016","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/27725201","citation_count":8,"is_preprint":false},{"pmid":"40016178","id":"PMC_40016178","title":"PSMD14-mediated deubiquitination of CARM1 facilitates the proliferation and metastasis of hepatocellular carcinoma by inducing the transcriptional activation of FERMT1.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40016178","citation_count":7,"is_preprint":false},{"pmid":"36505894","id":"PMC_36505894","title":"Identification of FERMT1 and SGCD as key marker in acute aortic dissection from the perspective of predictive, preventive, and personalized medicine.","date":"2022","source":"The EPMA journal","url":"https://pubmed.ncbi.nlm.nih.gov/36505894","citation_count":7,"is_preprint":false},{"pmid":"32973952","id":"PMC_32973952","title":"A novel frameshift mutation in the FERMT1 gene in a Chinese patient with Kindler syndrome.","date":"2020","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32973952","citation_count":5,"is_preprint":false},{"pmid":"26537214","id":"PMC_26537214","title":"A novel large deletion mutation of FERMT1 gene in a Chinese patient with Kindler syndrome.","date":"2015","source":"Journal of Zhejiang University. Science. B","url":"https://pubmed.ncbi.nlm.nih.gov/26537214","citation_count":5,"is_preprint":false},{"pmid":"39353234","id":"PMC_39353234","title":"FERMT1 promotes epithelial-mesenchymal transition of hepatocellular carcinoma by activating EGFR/AKT/β-catenin and EGFR/ERK pathways.","date":"2024","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39353234","citation_count":4,"is_preprint":false},{"pmid":"8428379","id":"PMC_8428379","title":"Yeast single copy gene URP1 is a homolog of rat ribosomal protein gene L21.","date":"1993","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8428379","citation_count":4,"is_preprint":false},{"pmid":"40044983","id":"PMC_40044983","title":"ITGB1/FERMT1 mechanoactivation enhances CD44 characteristic stemness in oral squamous cell carcinoma via ubiquitin-dependent CK1α degradation.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40044983","citation_count":3,"is_preprint":false},{"pmid":"38976072","id":"PMC_38976072","title":"FERMT1 suppression induces anti-tumor effects and reduces stemness in glioma cancer cells.","date":"2024","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38976072","citation_count":3,"is_preprint":false},{"pmid":"33683437","id":"PMC_33683437","title":"Examination of FERMT1 expression in placental chorionic villi and its role in HTR8-SVneo cell invasion.","date":"2021","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33683437","citation_count":3,"is_preprint":false},{"pmid":"39309641","id":"PMC_39309641","title":"Identification of a novel FERMT1 variant causing kindler syndrome and a review of the clinical and molecular genetic features in Chinese patients.","date":"2024","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/39309641","citation_count":2,"is_preprint":false},{"pmid":"31957900","id":"PMC_31957900","title":"A novel pathogenic FERMT1 variant in four families with Kindler syndrome in Argentina.","date":"2020","source":"Pediatric dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/31957900","citation_count":2,"is_preprint":false},{"pmid":"39488921","id":"PMC_39488921","title":"FERMT1 contributes to the epithelial-mesenchymal transition of chronic rhinosinusitis with nasal polyps via PI3K/Akt signaling.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39488921","citation_count":1,"is_preprint":false},{"pmid":"41093166","id":"PMC_41093166","title":"FERMT1 suppresses the ferroptosis of glioma cells by interacting with MBOAT2.","date":"2025","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/41093166","citation_count":1,"is_preprint":false},{"pmid":"27293055","id":"PMC_27293055","title":"A Novel Nonsense Mutation in Exon 5 of KIND1 Gene in an Iranian Family with Kindler Syndrome.","date":"2016","source":"Archives of Iranian medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27293055","citation_count":0,"is_preprint":false},{"pmid":"29265026","id":"PMC_29265026","title":"Evaluating KIND1 human embryonic stem cell-derived pancreatic progenitors to ameliorate streptozotocin-induced diabetes in mice.","date":"2017","source":"The Indian journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/29265026","citation_count":0,"is_preprint":false},{"pmid":"41674941","id":"PMC_41674941","title":"Multi-omics analysis links FERMT1 expression to patient survival, immunotherapy response, and metastasis across cancers.","date":"2026","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41674941","citation_count":0,"is_preprint":false},{"pmid":"40362475","id":"PMC_40362475","title":"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.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40362475","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.26.645566","title":"A Spatial Multi-Omic Framework Identifies Gliomas Permissive to TIL Expansion","date":"2025-03-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.26.645566","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19225,"output_tokens":3380,"usd":0.054187},"stage2":{"model":"claude-opus-4-6","input_tokens":6832,"output_tokens":2980,"usd":0.16299},"total_usd":0.217177,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Loss-of-function (Kindler syndrome patient keratinocytes), overexpression rescue, immunofluorescence, integrin activation assays\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal loss-of-function and gain-of-function with specific integrin activation readout, replicated in patient material\",\n      \"pmids\": [\"19762710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown in keratinocytes, cytokine profiling, co-culture experiments, Western blotting\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined paracrine signaling phenotype, single lab with multiple readouts\",\n      \"pmids\": [\"21309038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, nuclear fractionation, luciferase reporter assay, pharmacological epistasis, in vitro migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct Co-IP with epistasis via pharmacological Wnt modulation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27641329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, skin graft model in mice, UV irradiation, γH2AX and CPD immunofluorescence, pharmacological JNK/NF-κB inhibition, ChIP/promoter analysis for JunB regulation\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined DNA damage and signaling phenotypes, pharmacological epistasis, single lab\",\n      \"pmids\": [\"27725201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence localization, siRNA knockdown, invasion assay (Matrigel transwell), adhesion assay\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct localization with functional consequence via clean KD, single lab\",\n      \"pmids\": [\"33683437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase 3'-UTR reporter assay, miRNA overexpression, lentiviral FERMT1 overexpression, proliferation and radiation resistance assays\",\n      \"journal\": \"Journal of biomedical nanotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding confirmed by reporter assay plus rescue experiment, single lab\",\n      \"pmids\": [\"31165706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, ubiquitination assay, proteasome inhibitor treatment, siRNA knockdown, stiffness-controlled ECM experiments, Western blotting, in vivo tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway established by Co-IP, ubiquitination assay, and rescue experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40044983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence double staining, siRNA knockdown, Western blotting, pathway inhibitor rescue, in vivo xenograft and lung metastasis models\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct Co-IP confirmed interaction, pathway validated by inhibitors, single lab\",\n      \"pmids\": [\"39353234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, Western blotting, Transwell migration/invasion assays, epistasis by PKP3 knockdown\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — epistasis via double KD, multiple assays, single lab\",\n      \"pmids\": [\"38200443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, gain and loss-of-function experiments, erastin-induced ferroptosis assay, ferrostatin-1 rescue, MBOAT2 epistasis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP confirmed interaction plus epistasis by double manipulation, single lab\",\n      \"pmids\": [\"41093166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP for H3R17me2, siRNA/overexpression of CARM1, PSMD14 co-IP/ubiquitination assays, CARM1 inhibitor (SGC2085), in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-based epigenetic regulation with pharmacological and genetic validation, single lab with multiple methods\",\n      \"pmids\": [\"40016178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, Western blotting, Transwell assay, xenograft model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with limited mechanistic follow-up on the FERMT1–NLRP3 interaction, single lab\",\n      \"pmids\": [\"35144617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, FERMT1 overexpression, RNA sequencing, PI3K/Akt inhibitor treatment, mouse CRSwNP model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological epistasis without direct binding evidence, single lab\",\n      \"pmids\": [\"39488921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assay, RT-PCR/mRNA expression analysis in patient skin, deletion mapping\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reporter assay plus patient tissue validation, single lab\",\n      \"pmids\": [\"25156791\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FERMT1 (kindlin-1) is a focal adhesion FERM-domain protein that activates β1 integrins in epithelial cells, localizes to focal adhesions and the cell membrane, and mechanistically engages multiple signaling axes: it directly binds and activates β-catenin/Wnt signaling to drive EMT, interacts with EGFR to stimulate AKT and ERK pathways, acts downstream of ITGB1 mechanotransduction to promote CK1α degradation via MIB1 ubiquitin ligase, suppresses ferroptosis through interaction with MBOAT2, and is transcriptionally regulated by CARM1-mediated H3R17me2 histone methylation and by miR-24; loss-of-function causes Kindler syndrome through defective integrin activation, keratinocyte fragility, impaired DNA repair, and paracrine cytokine-driven dermal fibrosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Loss-of-function patient keratinocytes with overexpression rescue and integrin activation assays\",\n      \"pmids\": [\"19762710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FERMT1–integrin tail interaction not defined\", \"Relative contribution versus kindlin-2 in same cell type unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA knockdown in keratinocytes, cytokine profiling, and co-culture with dermal fibroblasts\",\n      \"pmids\": [\"21309038\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which cytokine(s) are necessary and sufficient not individually tested\", \"In vivo validation in conditional knockout model absent\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Luciferase reporter assay and RT-PCR in patient keratinocytes\",\n      \"pmids\": [\"25156791\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor(s) binding the affected promoter elements not identified in this study\", \"Genotype–phenotype correlation with different promoter variants not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, TCF/LEF luciferase reporter, pharmacological epistasis with Wnt activator/inhibitor, xenograft models in colon cancer cells\",\n      \"pmids\": [\"27641329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain on FERMT1 mediating β-catenin interaction not mapped\", \"Whether this mechanism operates in normal epithelium versus only cancer cells unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA knockdown, UV irradiation, γH2AX/CPD immunofluorescence, pharmacological JNK/NF-κB inhibition, ChIP for JunB at FERMT1 promoter\",\n      \"pmids\": [\"27725201\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect role of FERMT1 in DNA repair machinery not delineated\", \"Whether DNA repair defect contributes to Kindler syndrome cancer risk not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Luciferase 3′-UTR reporter assay, miRNA overexpression, lentiviral FERMT1 rescue in esophageal cancer cells\",\n      \"pmids\": [\"31165706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contexts in which miR-24–FERMT1 axis operates beyond cancer unknown\", \"Other miRNAs targeting FERMT1 not surveyed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, immunofluorescence co-localization, pathway inhibitor rescue, xenograft and lung metastasis models in hepatocellular carcinoma\",\n      \"pmids\": [\"39353234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding domain on EGFR and FERMT1 not mapped\", \"Whether FERMT1 affects EGFR internalization or surface stability not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, proteasome inhibitor treatment, stiffness-controlled ECM, in vivo OSCC model\",\n      \"pmids\": [\"40044983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FERMT1 directly binds MIB1 or CK1α individually not resolved\", \"Generalizability beyond oral squamous cell carcinoma not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"An unexpected anti-ferroptotic function was uncovered: FERMT1 interacts with lysophospholipid acyltransferase MBOAT2 to suppress ferroptosis, with full epistasis confirming MBOAT2 as the effector.\",\n      \"evidence\": \"Co-IP, erastin-induced ferroptosis assay, MBOAT2 epistasis (double manipulation), glioma cells\",\n      \"pmids\": [\"41093166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lipid species remodeled by FERMT1–MBOAT2 interaction not profiled\", \"Structural basis of FERMT1–MBOAT2 interaction unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP for H3R17me2, CARM1 siRNA/overexpression, PSMD14 Co-IP/ubiquitination assay, CARM1 inhibitor SGC2085 in HCC cells\",\n      \"pmids\": [\"40016178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CARM1–FERMT1 regulation operates in normal epithelial tissues not assessed\", \"Other epigenetic marks at the FERMT1 locus not surveyed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 6, 7]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ITGB1\", \"CTNNB1\", \"EGFR\", \"MBOAT2\", \"MIB1\", \"CSNK1A1\", \"PKP3\"],\n    \"other_free_text\": []\n  }\n}\n```"}