{"gene":"FERMT2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2003,"finding":"FERMT2 (Mig-2) localizes to cell-matrix adhesions, interacts with migfilin through Mig-2's C-terminal domain, and with filamin through migfilin's N-terminal domain. Mig-2 recruits migfilin to cell-matrix adhesions, and migfilin's interaction with filamin mediates its association with actin filaments. Loss of Mig-2 impairs cell shape modulation.","method":"Co-immunoprecipitation, pulldown assays, dominant-negative/loss-of-function cell experiments, localization by immunofluorescence","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and functional knockdown with defined cellular phenotype, replicated across multiple experiments in one rigorous study","pmids":["12679033"],"is_preprint":false},{"year":2007,"finding":"FERMT2 (Mig-2) binds directly to beta1 and beta3 integrin cytoplasmic domains via a single site within its FERM domain. This interaction recruits Mig-2 to focal adhesions, promotes integrin activation, and enhances cell-ECM adhesion. An integrin-binding-defective Mig-2 mutant fails to strengthen cell-matrix adhesion or reduce cell motility.","method":"Co-immunoprecipitation, site-directed mutagenesis of the FERM domain, integrin activation assays in CHO cells, cell adhesion and motility assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro binding assays with mutagenesis, functional rescue experiments, multiple orthogonal methods in one study","pmids":["17513299"],"is_preprint":false},{"year":2008,"finding":"FERMT2 (Kindlin-2) binds to the C-terminal region of integrin beta3 cytoplasmic tail (TS752T region and NITY759 motif) and functions as a co-activator of beta3 integrins. Co-transfection with talin head domain produces synergistic enhancement of alphaIIbbeta3 activation. siRNA knockdown of endogenous kindlin-2 impairs talin-induced alphaIIbbeta3 activation and blunts alphaVbeta3-mediated adhesion and migration.","method":"Co-immunoprecipitation, integrin activation assays (flow cytometry for PAC-1 binding), siRNA knockdown, cell adhesion/migration assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, siRNA knockdown with defined functional phenotype, and synergy experiment; independently validated by prior integrin binding study","pmids":["18458155"],"is_preprint":false},{"year":2016,"finding":"FERMT2 underexpression increases Abeta peptide production by raising levels of mature APP at the cell surface and facilitating its recycling, as shown by genome-wide high-content siRNA screening and follow-up mechanistic assays.","method":"Genome-wide high-content siRNA screening, APP metabolism assays, cell surface APP quantification, APP recycling assays","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional siRNA screen followed by mechanistic follow-up in single lab with multiple assays","pmids":["27933404"],"is_preprint":false},{"year":2018,"finding":"In podocytes, loss of FERMT2 results in altered cortical actin composition, cell cortex destabilization with plasma membrane blebbing, remodeling of focal adhesions, and elevated RhoA activation with increased actomyosin contractility. Inhibition of actomyosin tension reverses the membrane blebbing phenotype, linking FERMT2 to the regulation of plasma membrane tension via cell-matrix adhesion.","method":"Conditional FERMT2 knockout (in vivo and CRISPR/Cas9-modified human podocytes), RhoA activity assay, actomyosin inhibitor rescue experiments, actin fractionation, focal adhesion analysis","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout in multiple systems (in vivo + CRISPR human cells), pharmacological rescue, multiple orthogonal readouts in one study","pmids":["29337051"],"is_preprint":false},{"year":2019,"finding":"siRNA-mediated knockdown of FERMT2 in human iPSC-derived neurons reduces extracellular Abeta levels and reduces the proportion of phosphorylated TAU. CRISPR-Cas9 targeting of FERMT2 in familial AD human neurons validated reduced extracellular Abeta. In familial AD neurons, FERMT2 reduction elevated Abeta42:40 ratio with no reduction in phospho-TAU, revealing cell-context-dependent effects.","method":"shRNA knockdown, CRISPR-Cas9 knockout in iPSC-derived neurons, ELISA for extracellular Abeta, phospho-TAU immunoassay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype validated by two genetic methods in human neurons, single lab","pmids":["30371777"],"is_preprint":false},{"year":2018,"finding":"FERMT2 is prominently localized to extravillous trophoblast cell periphery. siRNA knockdown of FERMT2 in HTR8-SVneo trophoblast cells significantly decreases cell-substrate attachment and invasion, demonstrating a role in integrin-mediated trophoblast invasion.","method":"siRNA knockdown, cell-substrate adhesion assays, Matrigel invasion assays, immunofluorescence localization","journal":"BMC developmental biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — siRNA knockdown with two functional readouts plus localization, single lab","pmids":["30382829"],"is_preprint":false},{"year":2020,"finding":"FERMT2 directly interacts with APP to modulate its metabolism. FERMT2 underexpression impairs axonal growth, synaptic connectivity, and long-term potentiation in an APP-dependent manner. The rs7143400-T AD-risk allele in the FERMT2 3'UTR reduces FERMT2 expression through miR-4504 binding.","method":"Co-immunoprecipitation for FERMT2-APP interaction, genome-wide high-content screening, neuronal loss-of-function experiments (axon growth assay, LTP assay), luciferase reporter assay for miRNA binding","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Co-IP for interaction plus functional rescue in APP-dependent manner, multiple assays, single lab","pmids":["33144711"],"is_preprint":false},{"year":2014,"finding":"Mig-2 (FERMT2) attenuates cisplatin-induced apoptosis in glioma cells via AKT/JNK and AKT/p38 signaling pathways. The F3 subdomain of Mig-2 is necessary and sufficient for this anti-apoptotic effect; a mutant lacking F3 is inactive. Overexpression reduces cleaved caspases and p-JNK/p-p38 while increasing p-AKT.","method":"Plasmid overexpression, siRNA knockdown, domain deletion mutants (F3 subdomain), Western blotting, pharmacological inhibitors (SP600125, SB203580, LY294002), flow cytometry apoptosis assay","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — domain mutagenesis combined with pharmacological pathway validation across multiple cell lines, single lab","pmids":["25152024"],"is_preprint":false},{"year":2025,"finding":"KINDLIN2 (FERMT2) is a substrate of caspases and calpain I. These proteolytic cleavages dissociate the F0 and F1 domains of KINDLIN2 and decrease its ability to control APP processing, representing a potential mechanism regulating synaptic function relevant to AD pathophysiology.","method":"In vitro caspase/calpain cleavage assays, domain dissociation analysis, APP processing assays following KINDLIN2 cleavage","journal":"Neurobiology of aging","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro enzymatic assays with functional readout (APP processing), single lab, novel substrate identification","pmids":["40273529"],"is_preprint":false},{"year":2025,"finding":"FERMT2 promotes anoikis resistance in gastric cancer by suppressing ubiquitination of SOX2, thereby enhancing its stability and upregulating FN1 transcription and extracellular fibronectin matrix deposition. TGFbeta-RI forms a positive feedback loop with FERMT2 via TGFbeta-1/TGFbeta-RI signaling to drive this process.","method":"In vitro and in vivo functional assays, ubiquitination assay for SOX2, transcription assay for FN1, co-expression and knockdown experiments, peritoneal metastasis mouse model","journal":"Gastric cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissected with ubiquitination assay and in vivo model, single lab","pmids":["40024947"],"is_preprint":false},{"year":2026,"finding":"FERMT2 is required for YAP/TAZ nuclear accumulation and transcriptional activity in breast cancer cells. FERMT2 regulates YAP/TAZ independently of the canonical Hippo pathway through integrin-mediated activation of FAK; glucocorticoid-driven FAK activation restores YAP/TAZ signaling in FERMT2-depleted cells. FERMT2 also modulates actin-dependent regulation of YAP/TAZ.","method":"CRISPR/Cas9 loss-of-function screens (in vitro and in vivo), FERMT2 knockout and silencing, YAP/TAZ nuclear localization assays, YAP/TAZ target gene expression, FAK phosphorylation assays, pharmacological FAK activation rescue, epistasis analysis","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screens validated with KO/silencing and pharmacological rescue, multiple orthogonal methods, single lab","pmids":["41792242"],"is_preprint":false},{"year":2025,"finding":"In gastric cancer-associated fibroblasts, FERMT2 maintains the myofibroblastic phenotype by acting as a competing endogenous RNA (ceRNA) for ZEB2, thereby promoting alpha-SMA transcription. FERMT2 drives GCAF secretion of TGF-beta1, which in turn induces FERMT2 in tumor cells. Tumor-derived FERMT2 upregulates COL6A1 and facilitates its transfer to GCAFs via exosomes, reinforcing a TGF-beta1/FERMT2/COL6A1 positive feedback loop.","method":"Bulk and single-cell transcriptomics, functional assays, proteomics, in vivo peritoneal metastasis model, ceRNA analysis, exosome isolation and transfer experiments","journal":"International journal of biological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — multiple methods but complex mechanistic claims (ceRNA, exosome transfer) from single lab, abstract does not detail rigor of each step","pmids":["41079932"],"is_preprint":false}],"current_model":"FERMT2 (Kindlin-2/Mig-2) is a FERM-domain focal adhesion scaffold protein that binds directly to integrin beta cytoplasmic tails to co-activate integrins (synergizing with talin), recruits migfilin to cell-matrix adhesions linking them to filamin and the actin cytoskeleton, regulates RhoA/actomyosin contractility and membrane tension, controls YAP/TAZ nuclear activity via integrin-FAK signaling, directly interacts with APP to modulate its processing and Abeta production (with FERMT2 itself being a substrate of caspase/calpain cleavage that disrupts this function), and promotes cell survival and invasion through AKT/JNK/p38 and TGFbeta/SOX2/fibronectin pathways."},"narrative":{"mechanistic_narrative":"FERMT2 (Kindlin-2/Mig-2) is a FERM-domain focal adhesion scaffold that couples integrin-based cell-matrix adhesion to the actin cytoskeleton and downstream signaling [PMID:12679033, PMID:17513299]. It binds directly to the cytoplasmic tails of beta1 and beta3 integrins through a single site in its FERM domain, where it acts as a co-activator that synergizes with the talin head domain to drive integrin activation and strengthen cell-ECM adhesion while limiting motility [PMID:17513299, PMID:18458155]. In parallel, FERMT2 recruits migfilin to cell-matrix adhesions, linking these sites to filamin and actin filaments and enabling cell shape modulation [PMID:12679033]. Through this adhesion axis FERMT2 restrains RhoA-driven actomyosin contractility and stabilizes the cell cortex and plasma membrane tension [PMID:29337051], and it is required for integrin-FAK-dependent nuclear accumulation and transcriptional activity of YAP/TAZ independently of the canonical Hippo pathway [PMID:41792242]. These adhesion and survival functions underlie roles in trophoblast invasion [PMID:30382829] and in cancer, where FERMT2 attenuates apoptosis via AKT/JNK and AKT/p38 signaling [PMID:25152024] and promotes anoikis resistance and metastasis through TGFbeta/SOX2/FN1 signaling [PMID:40024947]. Independently, FERMT2 directly interacts with APP to modulate its surface trafficking, recycling, and processing, thereby controlling Abeta production and APP-dependent axonal growth, synaptic connectivity, and long-term potentiation; an AD-risk allele in its 3'UTR lowers FERMT2 expression via miR-4504, and proteolytic cleavage of FERMT2 by caspases and calpain disrupts its control of APP [PMID:27933404, PMID:33144711, PMID:30371777, PMID:40273529].","teleology":[{"year":2003,"claim":"Established FERMT2 as a cell-matrix adhesion scaffold by showing it physically bridges migfilin to filamin and actin, defining its first molecular role in adhesion architecture and cell shape.","evidence":"Reciprocal Co-IP, pulldowns, and loss-of-function with immunofluorescence localization","pmids":["12679033"],"confidence":"High","gaps":["Did not define how FERMT2 itself is recruited to adhesions","No structural detail of the FERMT2-migfilin interface"]},{"year":2007,"claim":"Identified the direct receptor link by mapping a single FERM-domain site that binds beta1/beta3 integrin tails, explaining how FERMT2 reaches adhesions and promotes integrin activation and adhesion strengthening.","evidence":"Co-IP, FERM-domain site-directed mutagenesis, integrin activation and adhesion/motility assays in CHO cells","pmids":["17513299"],"confidence":"High","gaps":["Did not resolve cooperation with talin","Mechanism coupling integrin binding to reduced motility unclear"]},{"year":2008,"claim":"Defined FERMT2 as a co-activator of integrins, showing it acts synergistically with the talin head to activate beta3 integrins rather than activating them alone.","evidence":"Co-IP, tail-region mapping, PAC-1 integrin activation flow cytometry, siRNA knockdown, adhesion/migration assays","pmids":["18458155"],"confidence":"High","gaps":["Stoichiometry/order of talin and FERMT2 binding not resolved","Generalization beyond alphaIIbbeta3/alphaVbeta3 untested"]},{"year":2014,"claim":"Connected FERMT2 to cell survival signaling, showing its F3 subdomain is necessary and sufficient to suppress cisplatin-induced apoptosis via AKT/JNK and AKT/p38 pathways.","evidence":"Overexpression, siRNA, F3 deletion mutants, pathway inhibitors, apoptosis flow cytometry in glioma cells","pmids":["25152024"],"confidence":"Medium","gaps":["Direct molecular link between F3 and AKT activation not defined","Single cancer context"]},{"year":2018,"claim":"Showed FERMT2 controls cytoskeletal mechanics, with its loss elevating RhoA/actomyosin contractility and destabilizing the cell cortex and membrane tension, extending its role from adhesion to mechanoregulation.","evidence":"Conditional knockout in vivo and CRISPR human podocytes, RhoA activity assay, actomyosin inhibitor rescue, actin fractionation","pmids":["29337051"],"confidence":"High","gaps":["How FERMT2 restrains RhoA mechanistically not defined","Link to specific focal adhesion components unresolved"]},{"year":2018,"claim":"Demonstrated a physiological invasion role, with FERMT2 required for integrin-mediated trophoblast attachment and Matrigel invasion.","evidence":"siRNA knockdown, adhesion and invasion assays, immunofluorescence in HTR8-SVneo trophoblasts","pmids":["30382829"],"confidence":"Medium","gaps":["Which integrins mediate the effect not specified","Single cell line"]},{"year":2016,"claim":"Linked FERMT2 to Alzheimer-relevant biology, showing its underexpression raises Abeta by increasing mature surface APP and its recycling.","evidence":"Genome-wide high-content siRNA screen with APP metabolism, surface APP, and recycling assays","pmids":["27933404"],"confidence":"Medium","gaps":["Did not establish direct FERMT2-APP physical interaction","Trafficking machinery involved unknown"]},{"year":2019,"claim":"Validated FERMT2's APP-modulating effect in human neurons while revealing cell-context dependence, with knockdown reducing Abeta and phospho-TAU but familial AD neurons showing an elevated Abeta42:40 ratio.","evidence":"shRNA and CRISPR-Cas9 in iPSC-derived neurons, Abeta ELISA, phospho-TAU immunoassay","pmids":["30371777"],"confidence":"Medium","gaps":["Basis of context-dependent opposite effects unresolved","No direct mechanism for TAU phosphorylation change"]},{"year":2020,"claim":"Defined the direct FERMT2-APP interaction and its functional consequences for neuronal connectivity, and identified an AD-risk 3'UTR variant that lowers FERMT2 via miR-4504.","evidence":"Co-IP, high-content screening, axon growth and LTP assays, miRNA luciferase reporter","pmids":["33144711"],"confidence":"Medium","gaps":["APP-binding region of FERMT2 not mapped","How adhesion functions intersect with APP regulation unclear"]},{"year":2025,"claim":"Identified FERMT2 as a caspase/calpain substrate whose cleavage dissociates F0/F1 domains and impairs its control of APP processing, providing a regulatory mechanism relevant to AD.","evidence":"In vitro caspase/calpain cleavage assays, domain dissociation analysis, APP processing assays","pmids":["40273529"],"confidence":"Medium","gaps":["Cleavage not yet demonstrated in vivo in neurons","Functional fate of cleavage fragments unknown"]},{"year":2025,"claim":"Extended FERMT2 cancer signaling to anoikis resistance and metastasis, showing it stabilizes SOX2 by blocking its ubiquitination to drive FN1/fibronectin deposition within a TGFbeta-RI feedback loop.","evidence":"In vitro/in vivo assays, SOX2 ubiquitination assay, FN1 transcription assay, peritoneal metastasis mouse model in gastric cancer","pmids":["40024947"],"confidence":"Medium","gaps":["Direct vs indirect control of SOX2 ubiquitination not resolved","Link between adhesion scaffold role and SOX2 stabilization unclear"]},{"year":2026,"claim":"Placed FERMT2 upstream of YAP/TAZ mechanotransduction, showing it drives YAP/TAZ nuclear activity through integrin-FAK signaling independent of the canonical Hippo pathway.","evidence":"CRISPR loss-of-function screens, KO/silencing, YAP/TAZ localization and target-gene assays, FAK phosphorylation, pharmacological FAK rescue, epistasis","pmids":["41792242"],"confidence":"Medium","gaps":["How FAK activation feeds into YAP/TAZ nuclear import not detailed","Relative contribution of actin-dependent vs FAK-dependent routes unresolved"]},{"year":null,"claim":"How FERMT2's core adhesion/mechanotransduction scaffold function mechanistically integrates with its distinct APP-processing and SOX2/YAP transcriptional roles, and whether these reflect a single biochemical activity or separable functions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model linking integrin, APP, and transcriptional partners","Cell-context determinants of opposite phenotypes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1,2,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,5,7]}],"complexes":["integrin-talin-kindlin adhesion complex"],"partners":["ITGB1","ITGB3","FERMT2","FLNA","TLN1","APP","SOX2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96AC1","full_name":"Fermitin family homolog 2","aliases":["Kindlin-2","Mitogen-inducible gene 2 protein","MIG-2","Pleckstrin homology domain-containing family C member 1","PH domain-containing family C member 1"],"length_aa":680,"mass_kda":77.9,"function":"Scaffolding protein that enhances integrin activation mediated by TLN1 and/or TLN2, but activates integrins only weakly by itself. Binds to membranes enriched in phosphoinositides. Enhances integrin-mediated cell adhesion onto the extracellular matrix and cell spreading; this requires both its ability to interact with integrins and with phospholipid membranes. Required for the assembly of focal adhesions. Participates in the connection between extracellular matrix adhesion sites and the actin cytoskeleton and also in the orchestration of actin assembly and cell shape modulation. Recruits FBLIM1 to focal adhesions. Plays a role in the TGFB1 and integrin signaling pathways. Stabilizes active CTNNB1 and plays a role in the regulation of transcription mediated by CTNNB1 and TCF7L2/TCF4 and in Wnt signaling","subcellular_location":"Cytoplasm; Cytoplasm, cell cortex; Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, stress fiber; Cell junction, focal adhesion; Membrane; Cell projection, lamellipodium membrane; Nucleus; Cytoplasm, myofibril, sarcomere, I band; Cell surface","url":"https://www.uniprot.org/uniprotkb/Q96AC1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FERMT2","classification":"Not Classified","n_dependent_lines":634,"n_total_lines":1208,"dependency_fraction":0.5248344370860927},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FERMT2","total_profiled":1310},"omim":[{"mim_id":"607901","title":"FERM DOMAIN-CONTAINING KINDLIN 3; FERMT3","url":"https://www.omim.org/entry/607901"},{"mim_id":"607746","title":"FERM DOMAIN-CONTAINING KINDLIN 2; FERMT2","url":"https://www.omim.org/entry/607746"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Focal adhesion sites","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FERMT2"},"hgnc":{"alias_symbol":["mig-2","KIND2","UNC112B"],"prev_symbol":["PLEKHC1"]},"alphafold":{"accession":"Q96AC1","domains":[{"cath_id":"3.10.20.90","chopping":"17-94","consensus_level":"high","plddt":94.6286,"start":17,"end":94},{"cath_id":"3.10.20.90","chopping":"97-147_162-173_216-308","consensus_level":"medium","plddt":85.3654,"start":97,"end":308},{"cath_id":"2.30.29.30","chopping":"373-480","consensus_level":"medium","plddt":90.3697,"start":373,"end":480},{"cath_id":"2.30.29.30","chopping":"570-676","consensus_level":"high","plddt":89.2843,"start":570,"end":676}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96AC1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96AC1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96AC1-F1-predicted_aligned_error_v6.png","plddt_mean":79.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FERMT2","jax_strain_url":"https://www.jax.org/strain/search?query=FERMT2"},"sequence":{"accession":"Q96AC1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96AC1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96AC1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96AC1"}},"corpus_meta":[{"pmid":"12679033","id":"PMC_12679033","title":"Migfilin 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Mig-2 recruits migfilin to cell-matrix adhesions, and migfilin's interaction with filamin mediates its association with actin filaments. Loss of Mig-2 impairs cell shape modulation.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, dominant-negative/loss-of-function cell experiments, localization by immunofluorescence\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and functional knockdown with defined cellular phenotype, replicated across multiple experiments in one rigorous study\",\n      \"pmids\": [\"12679033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FERMT2 (Mig-2) binds directly to beta1 and beta3 integrin cytoplasmic domains via a single site within its FERM domain. This interaction recruits Mig-2 to focal adhesions, promotes integrin activation, and enhances cell-ECM adhesion. An integrin-binding-defective Mig-2 mutant fails to strengthen cell-matrix adhesion or reduce cell motility.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of the FERM domain, integrin activation assays in CHO cells, cell adhesion and motility assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro binding assays with mutagenesis, functional rescue experiments, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17513299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FERMT2 (Kindlin-2) binds to the C-terminal region of integrin beta3 cytoplasmic tail (TS752T region and NITY759 motif) and functions as a co-activator of beta3 integrins. Co-transfection with talin head domain produces synergistic enhancement of alphaIIbbeta3 activation. siRNA knockdown of endogenous kindlin-2 impairs talin-induced alphaIIbbeta3 activation and blunts alphaVbeta3-mediated adhesion and migration.\",\n      \"method\": \"Co-immunoprecipitation, integrin activation assays (flow cytometry for PAC-1 binding), siRNA knockdown, cell adhesion/migration assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, siRNA knockdown with defined functional phenotype, and synergy experiment; independently validated by prior integrin binding study\",\n      \"pmids\": [\"18458155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FERMT2 underexpression increases Abeta peptide production by raising levels of mature APP at the cell surface and facilitating its recycling, as shown by genome-wide high-content siRNA screening and follow-up mechanistic assays.\",\n      \"method\": \"Genome-wide high-content siRNA screening, APP metabolism assays, cell surface APP quantification, APP recycling assays\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional siRNA screen followed by mechanistic follow-up in single lab with multiple assays\",\n      \"pmids\": [\"27933404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In podocytes, loss of FERMT2 results in altered cortical actin composition, cell cortex destabilization with plasma membrane blebbing, remodeling of focal adhesions, and elevated RhoA activation with increased actomyosin contractility. Inhibition of actomyosin tension reverses the membrane blebbing phenotype, linking FERMT2 to the regulation of plasma membrane tension via cell-matrix adhesion.\",\n      \"method\": \"Conditional FERMT2 knockout (in vivo and CRISPR/Cas9-modified human podocytes), RhoA activity assay, actomyosin inhibitor rescue experiments, actin fractionation, focal adhesion analysis\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout in multiple systems (in vivo + CRISPR human cells), pharmacological rescue, multiple orthogonal readouts in one study\",\n      \"pmids\": [\"29337051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"siRNA-mediated knockdown of FERMT2 in human iPSC-derived neurons reduces extracellular Abeta levels and reduces the proportion of phosphorylated TAU. CRISPR-Cas9 targeting of FERMT2 in familial AD human neurons validated reduced extracellular Abeta. In familial AD neurons, FERMT2 reduction elevated Abeta42:40 ratio with no reduction in phospho-TAU, revealing cell-context-dependent effects.\",\n      \"method\": \"shRNA knockdown, CRISPR-Cas9 knockout in iPSC-derived neurons, ELISA for extracellular Abeta, phospho-TAU immunoassay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype validated by two genetic methods in human neurons, single lab\",\n      \"pmids\": [\"30371777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FERMT2 is prominently localized to extravillous trophoblast cell periphery. siRNA knockdown of FERMT2 in HTR8-SVneo trophoblast cells significantly decreases cell-substrate attachment and invasion, demonstrating a role in integrin-mediated trophoblast invasion.\",\n      \"method\": \"siRNA knockdown, cell-substrate adhesion assays, Matrigel invasion assays, immunofluorescence localization\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — siRNA knockdown with two functional readouts plus localization, single lab\",\n      \"pmids\": [\"30382829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FERMT2 directly interacts with APP to modulate its metabolism. FERMT2 underexpression impairs axonal growth, synaptic connectivity, and long-term potentiation in an APP-dependent manner. The rs7143400-T AD-risk allele in the FERMT2 3'UTR reduces FERMT2 expression through miR-4504 binding.\",\n      \"method\": \"Co-immunoprecipitation for FERMT2-APP interaction, genome-wide high-content screening, neuronal loss-of-function experiments (axon growth assay, LTP assay), luciferase reporter assay for miRNA binding\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP for interaction plus functional rescue in APP-dependent manner, multiple assays, single lab\",\n      \"pmids\": [\"33144711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mig-2 (FERMT2) attenuates cisplatin-induced apoptosis in glioma cells via AKT/JNK and AKT/p38 signaling pathways. The F3 subdomain of Mig-2 is necessary and sufficient for this anti-apoptotic effect; a mutant lacking F3 is inactive. Overexpression reduces cleaved caspases and p-JNK/p-p38 while increasing p-AKT.\",\n      \"method\": \"Plasmid overexpression, siRNA knockdown, domain deletion mutants (F3 subdomain), Western blotting, pharmacological inhibitors (SP600125, SB203580, LY294002), flow cytometry apoptosis assay\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — domain mutagenesis combined with pharmacological pathway validation across multiple cell lines, single lab\",\n      \"pmids\": [\"25152024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KINDLIN2 (FERMT2) is a substrate of caspases and calpain I. These proteolytic cleavages dissociate the F0 and F1 domains of KINDLIN2 and decrease its ability to control APP processing, representing a potential mechanism regulating synaptic function relevant to AD pathophysiology.\",\n      \"method\": \"In vitro caspase/calpain cleavage assays, domain dissociation analysis, APP processing assays following KINDLIN2 cleavage\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro enzymatic assays with functional readout (APP processing), single lab, novel substrate identification\",\n      \"pmids\": [\"40273529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FERMT2 promotes anoikis resistance in gastric cancer by suppressing ubiquitination of SOX2, thereby enhancing its stability and upregulating FN1 transcription and extracellular fibronectin matrix deposition. TGFbeta-RI forms a positive feedback loop with FERMT2 via TGFbeta-1/TGFbeta-RI signaling to drive this process.\",\n      \"method\": \"In vitro and in vivo functional assays, ubiquitination assay for SOX2, transcription assay for FN1, co-expression and knockdown experiments, peritoneal metastasis mouse model\",\n      \"journal\": \"Gastric cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissected with ubiquitination assay and in vivo model, single lab\",\n      \"pmids\": [\"40024947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FERMT2 is required for YAP/TAZ nuclear accumulation and transcriptional activity in breast cancer cells. FERMT2 regulates YAP/TAZ independently of the canonical Hippo pathway through integrin-mediated activation of FAK; glucocorticoid-driven FAK activation restores YAP/TAZ signaling in FERMT2-depleted cells. FERMT2 also modulates actin-dependent regulation of YAP/TAZ.\",\n      \"method\": \"CRISPR/Cas9 loss-of-function screens (in vitro and in vivo), FERMT2 knockout and silencing, YAP/TAZ nuclear localization assays, YAP/TAZ target gene expression, FAK phosphorylation assays, pharmacological FAK activation rescue, epistasis analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screens validated with KO/silencing and pharmacological rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"41792242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In gastric cancer-associated fibroblasts, FERMT2 maintains the myofibroblastic phenotype by acting as a competing endogenous RNA (ceRNA) for ZEB2, thereby promoting alpha-SMA transcription. FERMT2 drives GCAF secretion of TGF-beta1, which in turn induces FERMT2 in tumor cells. Tumor-derived FERMT2 upregulates COL6A1 and facilitates its transfer to GCAFs via exosomes, reinforcing a TGF-beta1/FERMT2/COL6A1 positive feedback loop.\",\n      \"method\": \"Bulk and single-cell transcriptomics, functional assays, proteomics, in vivo peritoneal metastasis model, ceRNA analysis, exosome isolation and transfer experiments\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — multiple methods but complex mechanistic claims (ceRNA, exosome transfer) from single lab, abstract does not detail rigor of each step\",\n      \"pmids\": [\"41079932\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FERMT2 (Kindlin-2/Mig-2) is a FERM-domain focal adhesion scaffold protein that binds directly to integrin beta cytoplasmic tails to co-activate integrins (synergizing with talin), recruits migfilin to cell-matrix adhesions linking them to filamin and the actin cytoskeleton, regulates RhoA/actomyosin contractility and membrane tension, controls YAP/TAZ nuclear activity via integrin-FAK signaling, directly interacts with APP to modulate its processing and Abeta production (with FERMT2 itself being a substrate of caspase/calpain cleavage that disrupts this function), and promotes cell survival and invasion through AKT/JNK/p38 and TGFbeta/SOX2/fibronectin pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FERMT2 (Kindlin-2/Mig-2) is a FERM-domain focal adhesion scaffold that couples integrin-based cell-matrix adhesion to the actin cytoskeleton and downstream signaling [#0, #1]. It binds directly to the cytoplasmic tails of beta1 and beta3 integrins through a single site in its FERM domain, where it acts as a co-activator that synergizes with the talin head domain to drive integrin activation and strengthen cell-ECM adhesion while limiting motility [#1, #2]. In parallel, FERMT2 recruits migfilin to cell-matrix adhesions, linking these sites to filamin and actin filaments and enabling cell shape modulation [#0]. Through this adhesion axis FERMT2 restrains RhoA-driven actomyosin contractility and stabilizes the cell cortex and plasma membrane tension [#4], and it is required for integrin-FAK-dependent nuclear accumulation and transcriptional activity of YAP/TAZ independently of the canonical Hippo pathway [#11]. These adhesion and survival functions underlie roles in trophoblast invasion [#6] and in cancer, where FERMT2 attenuates apoptosis via AKT/JNK and AKT/p38 signaling [#8] and promotes anoikis resistance and metastasis through TGFbeta/SOX2/FN1 signaling [#10]. Independently, FERMT2 directly interacts with APP to modulate its surface trafficking, recycling, and processing, thereby controlling Abeta production and APP-dependent axonal growth, synaptic connectivity, and long-term potentiation; an AD-risk allele in its 3'UTR lowers FERMT2 expression via miR-4504, and proteolytic cleavage of FERMT2 by caspases and calpain disrupts its control of APP [#3, #7, #5, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established FERMT2 as a cell-matrix adhesion scaffold by showing it physically bridges migfilin to filamin and actin, defining its first molecular role in adhesion architecture and cell shape.\",\n      \"evidence\": \"Reciprocal Co-IP, pulldowns, and loss-of-function with immunofluorescence localization\",\n      \"pmids\": [\"12679033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how FERMT2 itself is recruited to adhesions\", \"No structural detail of the FERMT2-migfilin interface\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified the direct receptor link by mapping a single FERM-domain site that binds beta1/beta3 integrin tails, explaining how FERMT2 reaches adhesions and promotes integrin activation and adhesion strengthening.\",\n      \"evidence\": \"Co-IP, FERM-domain site-directed mutagenesis, integrin activation and adhesion/motility assays in CHO cells\",\n      \"pmids\": [\"17513299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve cooperation with talin\", \"Mechanism coupling integrin binding to reduced motility unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined FERMT2 as a co-activator of integrins, showing it acts synergistically with the talin head to activate beta3 integrins rather than activating them alone.\",\n      \"evidence\": \"Co-IP, tail-region mapping, PAC-1 integrin activation flow cytometry, siRNA knockdown, adhesion/migration assays\",\n      \"pmids\": [\"18458155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry/order of talin and FERMT2 binding not resolved\", \"Generalization beyond alphaIIbbeta3/alphaVbeta3 untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected FERMT2 to cell survival signaling, showing its F3 subdomain is necessary and sufficient to suppress cisplatin-induced apoptosis via AKT/JNK and AKT/p38 pathways.\",\n      \"evidence\": \"Overexpression, siRNA, F3 deletion mutants, pathway inhibitors, apoptosis flow cytometry in glioma cells\",\n      \"pmids\": [\"25152024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between F3 and AKT activation not defined\", \"Single cancer context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed FERMT2 controls cytoskeletal mechanics, with its loss elevating RhoA/actomyosin contractility and destabilizing the cell cortex and membrane tension, extending its role from adhesion to mechanoregulation.\",\n      \"evidence\": \"Conditional knockout in vivo and CRISPR human podocytes, RhoA activity assay, actomyosin inhibitor rescue, actin fractionation\",\n      \"pmids\": [\"29337051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FERMT2 restrains RhoA mechanistically not defined\", \"Link to specific focal adhesion components unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a physiological invasion role, with FERMT2 required for integrin-mediated trophoblast attachment and Matrigel invasion.\",\n      \"evidence\": \"siRNA knockdown, adhesion and invasion assays, immunofluorescence in HTR8-SVneo trophoblasts\",\n      \"pmids\": [\"30382829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which integrins mediate the effect not specified\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked FERMT2 to Alzheimer-relevant biology, showing its underexpression raises Abeta by increasing mature surface APP and its recycling.\",\n      \"evidence\": \"Genome-wide high-content siRNA screen with APP metabolism, surface APP, and recycling assays\",\n      \"pmids\": [\"27933404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish direct FERMT2-APP physical interaction\", \"Trafficking machinery involved unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Validated FERMT2's APP-modulating effect in human neurons while revealing cell-context dependence, with knockdown reducing Abeta and phospho-TAU but familial AD neurons showing an elevated Abeta42:40 ratio.\",\n      \"evidence\": \"shRNA and CRISPR-Cas9 in iPSC-derived neurons, Abeta ELISA, phospho-TAU immunoassay\",\n      \"pmids\": [\"30371777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis of context-dependent opposite effects unresolved\", \"No direct mechanism for TAU phosphorylation change\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the direct FERMT2-APP interaction and its functional consequences for neuronal connectivity, and identified an AD-risk 3'UTR variant that lowers FERMT2 via miR-4504.\",\n      \"evidence\": \"Co-IP, high-content screening, axon growth and LTP assays, miRNA luciferase reporter\",\n      \"pmids\": [\"33144711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"APP-binding region of FERMT2 not mapped\", \"How adhesion functions intersect with APP regulation unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified FERMT2 as a caspase/calpain substrate whose cleavage dissociates F0/F1 domains and impairs its control of APP processing, providing a regulatory mechanism relevant to AD.\",\n      \"evidence\": \"In vitro caspase/calpain cleavage assays, domain dissociation analysis, APP processing assays\",\n      \"pmids\": [\"40273529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage not yet demonstrated in vivo in neurons\", \"Functional fate of cleavage fragments unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended FERMT2 cancer signaling to anoikis resistance and metastasis, showing it stabilizes SOX2 by blocking its ubiquitination to drive FN1/fibronectin deposition within a TGFbeta-RI feedback loop.\",\n      \"evidence\": \"In vitro/in vivo assays, SOX2 ubiquitination assay, FN1 transcription assay, peritoneal metastasis mouse model in gastric cancer\",\n      \"pmids\": [\"40024947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect control of SOX2 ubiquitination not resolved\", \"Link between adhesion scaffold role and SOX2 stabilization unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed FERMT2 upstream of YAP/TAZ mechanotransduction, showing it drives YAP/TAZ nuclear activity through integrin-FAK signaling independent of the canonical Hippo pathway.\",\n      \"evidence\": \"CRISPR loss-of-function screens, KO/silencing, YAP/TAZ localization and target-gene assays, FAK phosphorylation, pharmacological FAK rescue, epistasis\",\n      \"pmids\": [\"41792242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How FAK activation feeds into YAP/TAZ nuclear import not detailed\", \"Relative contribution of actin-dependent vs FAK-dependent routes unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FERMT2's core adhesion/mechanotransduction scaffold function mechanistically integrates with its distinct APP-processing and SOX2/YAP transcriptional roles, and whether these reflect a single biochemical activity or separable functions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model linking integrin, APP, and transcriptional partners\", \"Cell-context determinants of opposite phenotypes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 5, 7]}\n    ],\n    \"complexes\": [\"integrin-talin-kindlin adhesion complex\"],\n    \"partners\": [\"ITGB1\", \"ITGB3\", \"FERMT2\", \"FLNA\", \"TLN1\", \"APP\", \"SOX2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}