{"gene":"FERMT2","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2003,"finding":"Migfilin (FERMT2) localizes to cell-matrix adhesions, interacts with Mig-2 (kindlin-2/FERMT2 family member UNC-112 homolog) through its C-terminal domain and with filamin through its N-terminal domain, linking cell-matrix adhesions to the actin cytoskeleton; loss of migfilin impairs cell shape modulation.","method":"Co-immunoprecipitation, pulldown assays, dominant-negative and loss-of-function experiments, live imaging of focal adhesion localization","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, domain mapping, loss-of-function with defined phenotype; foundational paper with 309 citations","pmids":["12679033"],"is_preprint":false},{"year":2008,"finding":"Kindlin-2 (FERMT2/Mig-2) binds to the C-terminal region of integrin β3 cytoplasmic tail (TS752T region and NITY759 motif) via its PTB domain and functions as a co-activator of β3 integrins, synergizing with talin head domain to activate αIIbβ3; siRNA knockdown impairs talin-induced αIIbβ3 activation and αvβ3-mediated adhesion and migration.","method":"In vitro binding assays, co-transfection/co-activation assays in CHO cells, siRNA knockdown with flow cytometry readout of integrin activation, cell adhesion and migration assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding assay + mutagenesis of integrin tail + functional rescue; 283 citations, replicated across multiple cell types","pmids":["18458155"],"is_preprint":false},{"year":2007,"finding":"FERMT2/Mig-2 interacts directly with β1 and β3 integrin cytoplasmic domains via a single site within its FERM domain; this interaction recruits Mig-2 to focal adhesions, promotes integrin activation, enhances cell-ECM adhesion, and reduces cell motility; an integrin-binding-defective mutant fails to rescue these functions.","method":"Pulldown assays with integrin cytoplasmic tail peptides, domain mutagenesis, αIIbβ3 activation assay in CHO cells, focal adhesion formation imaging, cell motility assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro binding with mutagenesis + multiple functional readouts; 148 citations","pmids":["17513299"],"is_preprint":false},{"year":2016,"finding":"FERMT2 (a β3-integrin co-activator) modulates APP metabolism: FERMT2 underexpression increases mature APP levels at the cell surface by facilitating APP recycling, leading to increased Aβ peptide production.","method":"Genome-wide high-content siRNA screen, cell-surface APP quantification, APP recycling assays, CSF Aβ correlation in AD cases","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide screen followed by targeted validation with multiple readouts; single lab","pmids":["27933404"],"is_preprint":false},{"year":2018,"finding":"FERMT2 loss in podocytes leads to altered cortical actin composition, plasma membrane blebbing, remodeling of focal adhesions, and elevated RhoA activation with increased actomyosin contractility; inhibition of actomyosin tension reverses the blebbing phenotype, establishing a direct link between FERMT2-mediated cell-matrix adhesion, cortical actin, and plasma membrane tension.","method":"Conditional genetic knockout (CRISPR/Cas9 in human podocytes and in vivo mouse models), RhoA activity assay, actomyosin inhibitor rescue, actin fractionation, focal adhesion imaging","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, multiple orthogonal assays, pharmacological rescue","pmids":["29337051"],"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 AD-risk allele rs7143400-T reduces FERMT2 expression via miR-4504 binding to the 3'UTR.","method":"Co-immunoprecipitation of FERMT2 and APP, genome-wide high-content screens, shRNA knockdown in neurons with axonal growth and LTP readouts, luciferase 3'UTR reporter assays for miR-4504","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 — direct protein-protein interaction by Co-IP, functional rescue experiments, two independent genome-wide screens, miRNA mechanism validated by reporter assay","pmids":["33144711"],"is_preprint":false},{"year":2019,"finding":"FERMT2 knockdown in human iPSC-derived neurons reduces extracellular Aβ levels and the proportion of phosphorylated TAU; CRISPR-Cas9 targeting of FERMT2 in familial AD neurons elevated Aβ42:40 ratio, demonstrating cell-type-specific and genetic-background-dependent effects on amyloid and tau proteostasis.","method":"shRNA lentiviral knockdown, CRISPR-Cas9 knockout in iPSC-derived neurons, ELISA for Aβ and phospho-tau","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO/KD in human neurons with defined molecular readouts; single lab","pmids":["30371777"],"is_preprint":false},{"year":2014,"finding":"Mig-2/FERMT2 attenuates cisplatin-induced apoptosis in glioma cells through AKT/JNK and AKT/p38 signaling; the F3 subdomain of Mig-2 is necessary and sufficient for this anti-apoptotic effect, as shown by domain-deletion mutagenesis.","method":"Plasmid overexpression and siRNA knockdown, Annexin V/PI apoptosis assay, Western blotting of caspase and signaling proteins, kinase inhibitor pharmacology, F3-domain and deletion mutant transfection","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — domain mutagenesis combined with pharmacological pathway inhibition; single lab","pmids":["25152024"],"is_preprint":false},{"year":2018,"finding":"FERMT2 is required for trophoblast-substrate adhesion and invasion; siRNA-mediated knockdown of FERMT2 in HTR8-SVneo cells significantly decreased cell-substrate attachment and invasive capacity, consistent with its role as an integrin activator in extravillous trophoblasts.","method":"siRNA knockdown, cell-substrate adhesion assay, invasion assay (Matrigel), immunofluorescence localization","journal":"BMC developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with two functional readouts; single lab, single method per assay","pmids":["30382829"],"is_preprint":false},{"year":2025,"finding":"KINDLIN2/FERMT2 is a substrate of caspases and calpain I; these cleavages dissociate the F0 and F1 domains of KINDLIN2 and reduce its ability to control APP processing, representing a regulatory mechanism of KINDLIN2 function at the synapse relevant to AD pathophysiology.","method":"In vitro caspase and calpain cleavage assays, domain-dissociation analysis, APP processing assays after protease treatment","journal":"Neurobiology of aging","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro biochemical cleavage assay with domain mapping; single lab, single study","pmids":["40273529"],"is_preprint":false},{"year":2025,"finding":"FERMT2 promotes anoikis resistance and peritoneal metastasis in gastric cancer by suppressing ubiquitination of SOX2 (stabilizing it), which upregulates FN1 transcription and drives fibronectin matrix deposition; TGFβ-1/TGFβ-RI signaling forms a positive feedback loop with FERMT2 to reinforce this mechanism.","method":"In vitro suspension assays, ubiquitination assays, ChIP/transcription reporter for FN1, in vivo peritoneal metastasis mouse models, TGFβ pathway inhibitors","journal":"Gastric cancer","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway defined by ubiquitination assay + transcriptional readout + in vivo validation; single lab","pmids":["40024947"],"is_preprint":false},{"year":2026,"finding":"FERMT2 is required for YAP/TAZ nuclear accumulation, YAP/TAZ target gene expression, and phosphorylation at key tyrosine residues in breast cancer cells; mechanistically, 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; partial epistasis also indicates actin-dependent regulation of YAP/TAZ by FERMT2.","method":"CRISPR/Cas9 loss-of-function screens (in vitro and in vivo), FERMT2 knockout and silencing, YAP/TAZ nuclear localization assay, phospho-FAK western blotting, FAK activator rescue, epistasis analysis","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — CRISPR screen + targeted KO + pathway epistasis + pharmacological rescue; multiple orthogonal methods in single study","pmids":["41792242"],"is_preprint":false},{"year":2022,"finding":"FERMT2 promotes colorectal carcinoma progression via the Wnt/β-catenin signaling pathway; overexpression of FERMT2 upregulates Wnt/β-catenin components, while FERMT2 knockdown suppresses migration, invasion, and EMT, effects that are rescued by β-catenin overexpression.","method":"FERMT2 overexpression and siRNA knockdown, Western blotting for Wnt/β-catenin proteins, migration/invasion assays, β-catenin rescue experiment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis by rescue experiment; single lab","pmids":["36480537"],"is_preprint":false},{"year":2025,"finding":"FERMT2 maintains the myofibroblastic phenotype of gastric cancer-associated fibroblasts by acting as a ceRNA for ZEB2, promoting α-SMA transcription; FERMT2 also drives GCAF-derived TGF-β1 secretion, and tumor-derived FERMT2 upregulates COL6A1 which is transferred to GCAFs via exosomes to amplify TGF-β signaling in a positive feedback loop.","method":"ceRNA/luciferase reporter assays, α-SMA transcription analysis, ELISA for TGF-β1, exosome isolation and transfer assays, co-culture functional assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — multiple molecular mechanisms tested with orthogonal methods; single lab","pmids":["41079932"],"is_preprint":false}],"current_model":"FERMT2/Kindlin-2 is a FERM domain-containing focal adhesion scaffold protein that co-activates β1 and β3 integrins by binding their cytoplasmic tails, links cell-matrix adhesions to the actin cytoskeleton (via filamin and migfilin interactions), modulates RhoA/actomyosin contractility and plasma membrane tension, activates YAP/TAZ through integrin-FAK signaling, directly interacts with APP to regulate its surface trafficking and Aβ production (with its function further tuned by caspase/calpain cleavage of its F0-F1 domains), and promotes cancer progression through Wnt/β-catenin, TGFβ, and SOX2-FN1 axes."},"narrative":{"teleology":[{"year":2003,"claim":"Identifying FERMT2's first interacting partners established that focal adhesion scaffolding — rather than enzymatic activity — is its primary molecular role, answering how cell-matrix adhesions connect to the actin cytoskeleton through the migfilin–filamin axis.","evidence":"Co-immunoprecipitation, pulldown assays, and dominant-negative experiments in cultured cells showing migfilin bridges FERMT2 to filamin and actin","pmids":["12679033"],"confidence":"High","gaps":["Integrin-binding mechanism of FERMT2 not yet characterized","Whether FERMT2 directly activates integrins or only scaffolds was unknown"]},{"year":2007,"claim":"Mapping FERMT2's FERM domain as the direct binding interface for β1 and β3 integrin cytoplasmic tails resolved how FERMT2 is recruited to focal adhesions and demonstrated that this interaction promotes integrin activation and cell-ECM adhesion.","evidence":"Pulldown assays with integrin tail peptides, domain mutagenesis, αIIbβ3 activation in CHO cells, focal adhesion imaging","pmids":["17513299"],"confidence":"High","gaps":["Whether FERMT2 synergizes with talin for integrin activation was not addressed","Structural basis of the FERM–integrin tail interaction at atomic resolution was lacking"]},{"year":2008,"claim":"Demonstrating that FERMT2 synergizes with talin head domain to co-activate αIIbβ3 and that its PTB domain recognizes specific motifs (NITY759) in the β3 tail established the talin–kindlin cooperativity model of inside-out integrin signaling.","evidence":"In vitro binding assays, co-transfection of talin head + FERMT2 in CHO cells, siRNA knockdown with flow cytometry integrin activation readout","pmids":["18458155"],"confidence":"High","gaps":["How FERMT2 and talin simultaneously engage the same integrin tail sterically was unresolved","Relevance to β1-integrin co-activation in non-hematopoietic cells not directly tested"]},{"year":2014,"claim":"Identifying the F3 subdomain as necessary and sufficient for AKT/JNK-dependent anti-apoptotic signaling revealed that FERMT2 has signaling functions beyond mechanical adhesion scaffolding.","evidence":"Overexpression/siRNA in glioma cells, domain-deletion mutagenesis, kinase inhibitor pharmacology, apoptosis assays","pmids":["25152024"],"confidence":"Medium","gaps":["Direct binding partner for F3 in the AKT pathway not identified","Whether this anti-apoptotic function is integrin-dependent was not determined"]},{"year":2016,"claim":"A genome-wide siRNA screen uncovered an unexpected role for FERMT2 in APP metabolism, showing that FERMT2 underexpression increases cell-surface mature APP and Aβ production — the first link between FERMT2 and Alzheimer's disease biology.","evidence":"High-content siRNA screen, cell-surface APP quantification, APP recycling assays, CSF Aβ correlation","pmids":["27933404"],"confidence":"Medium","gaps":["Whether FERMT2 directly binds APP or acts indirectly through integrins was unknown","Mechanism of APP recycling regulation by FERMT2 not defined"]},{"year":2018,"claim":"FERMT2 loss in podocytes was shown to elevate RhoA activation and actomyosin contractility, causing membrane blebbing reversible by actomyosin inhibition — establishing FERMT2 as a negative regulator of RhoA-dependent cortical tension downstream of integrin adhesion.","evidence":"CRISPR KO in human podocytes and conditional mouse KO, RhoA activity assay, pharmacological rescue with actomyosin inhibitors","pmids":["29337051"],"confidence":"High","gaps":["Identity of the RhoGEF or RhoGAP regulated by FERMT2 not determined","Whether this mechanism operates in cell types beyond podocytes was untested"]},{"year":2019,"claim":"Validation in iPSC-derived neurons showed that FERMT2 modulates both Aβ and phospho-tau levels, but with direction depending on genetic background (knockdown reduces Aβ in wild-type neurons; CRISPR KO in familial AD neurons elevates Aβ42:40 ratio), highlighting context-dependent effects.","evidence":"shRNA and CRISPR-Cas9 in iPSC-derived neurons, ELISA for Aβ species and phospho-tau","pmids":["30371777"],"confidence":"Medium","gaps":["Mechanism underlying opposing effects in different genetic backgrounds not resolved","Whether tau phosphorylation is a direct or indirect consequence of FERMT2 loss unclear"]},{"year":2020,"claim":"Demonstrating direct FERMT2–APP protein interaction by Co-IP, and showing that FERMT2 underexpression impairs axonal growth, synaptic connectivity, and LTP in an APP-dependent manner, established FERMT2 as a direct regulator of APP function in neurons; the AD-risk SNP rs7143400-T was shown to reduce FERMT2 expression via miR-4504.","evidence":"Co-immunoprecipitation, genome-wide screens, shRNA in neurons with axonal/LTP readouts, luciferase 3'UTR reporter for miR-4504","pmids":["33144711"],"confidence":"High","gaps":["Binding interface between FERMT2 and APP not mapped at domain level","Whether integrin co-activation is required for the FERMT2–APP interaction not tested"]},{"year":2022,"claim":"Epistasis experiments in colorectal carcinoma cells showed that FERMT2 drives migration, invasion, and EMT through the Wnt/β-catenin pathway, with β-catenin overexpression rescuing FERMT2-knockdown phenotypes — establishing a second oncogenic signaling axis for FERMT2.","evidence":"FERMT2 overexpression/knockdown, Wnt/β-catenin western blotting, β-catenin rescue of migration and invasion","pmids":["36480537"],"confidence":"Medium","gaps":["Whether FERMT2 regulates β-catenin via integrin-dependent or integrin-independent mechanism unknown","Direct molecular link between FERMT2 and β-catenin stabilization not identified"]},{"year":2025,"claim":"Caspase and calpain I were identified as proteases that cleave FERMT2 between its F0 and F1 domains, reducing its control of APP processing — revealing a post-translational regulatory mechanism relevant to neurodegeneration.","evidence":"In vitro caspase/calpain cleavage assays, domain-dissociation analysis, APP processing readouts","pmids":["40273529"],"confidence":"Medium","gaps":["In vivo relevance of FERMT2 cleavage at the synapse not demonstrated","Cleavage site residues not precisely mapped"]},{"year":2025,"claim":"In gastric cancer, FERMT2 was shown to stabilize SOX2 by suppressing its ubiquitination, leading to FN1 transcriptional upregulation and anoikis resistance, with TGFβ-1/TGFβ-RI forming a positive feedback loop — defining a complete FERMT2–SOX2–FN1–TGFβ signaling circuit for peritoneal metastasis.","evidence":"Ubiquitination assays, ChIP/reporter for FN1, in vivo peritoneal metastasis models, TGFβ inhibitor experiments","pmids":["40024947"],"confidence":"Medium","gaps":["Whether FERMT2 directly binds SOX2 or acts through an E3 ligase intermediate not resolved","Generalizability to cancers beyond gastric not tested"]},{"year":2025,"claim":"FERMT2 was shown to activate YAP/TAZ nuclear accumulation through integrin–FAK signaling independently of canonical Hippo kinases LATS1/2, with glucocorticoid-driven FAK activation rescuing YAP/TAZ in FERMT2-depleted cells — establishing a Hippo-independent mechanotransduction pathway in breast cancer.","evidence":"CRISPR screen (in vitro and in vivo), FERMT2 KO, phospho-FAK blotting, FAK activator rescue, epistasis analysis","pmids":["41792242"],"confidence":"High","gaps":["How FAK phosphorylation leads to YAP tyrosine phosphorylation at specific residues not mapped","Whether this Hippo-independent YAP regulation applies to non-malignant cells not tested"]},{"year":null,"claim":"Key open questions include the structural basis of simultaneous FERMT2–talin–integrin engagement, the direct binding interface between FERMT2 and APP, the identity of RhoGEFs/GAPs linking FERMT2 to RhoA, and whether FERMT2's diverse signaling outputs (Wnt, TGFβ, YAP/TAZ) are all integrin-dependent or reflect integrin-independent scaffolding functions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of FERMT2 in complex with integrin tail and talin","Binding interface between FERMT2 and APP not mapped","Whether Wnt/β-catenin and SOX2 stabilization functions require integrin binding unknown"]}],"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":[1,2,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,3,4]},{"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":[0,2,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,11,12]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,12,13]}],"complexes":["Integrin-kindlin-talin adhesion complex"],"partners":["ITGB3","ITGB1","TLN1","FLNA","FBLIM1","APP","SOX2","PTK2"],"other_free_text":[]},"mechanistic_narrative":"FERMT2 (Kindlin-2) is a FERM domain-containing focal adhesion protein that co-activates β1 and β3 integrins, couples integrin-mediated adhesion to the actin cytoskeleton, and transduces mechanical and signaling cues to downstream effector pathways including RhoA/actomyosin, FAK–YAP/TAZ, Wnt/β-catenin, and TGFβ signaling. FERMT2 binds integrin β-subunit cytoplasmic tails through its PTB/FERM domain, synergizes with talin to drive integrin activation, and connects to the actin cytoskeleton via interactions with migfilin and filamin; loss of FERMT2 causes aberrant RhoA activation, membrane blebbing, and impaired adhesion and migration [PMID:12679033, PMID:18458155, PMID:17513299, PMID:29337051]. FERMT2 directly interacts with APP to regulate its surface trafficking and Aβ production, and caspase/calpain-mediated cleavage of its F0–F1 domains modulates this activity, linking FERMT2 to Alzheimer's disease-associated amyloid and tau proteostasis [PMID:33144711, PMID:40273529, PMID:30371777]. In cancer contexts, FERMT2 activates YAP/TAZ nuclear accumulation through integrin–FAK signaling independently of canonical Hippo kinases, stabilizes SOX2 to upregulate fibronectin and promote anoikis resistance, and drives Wnt/β-catenin-dependent epithelial–mesenchymal transition [PMID:41792242, PMID:40024947, PMID:36480537]."},"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 and Mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12679033","citation_count":309,"is_preprint":false},{"pmid":"18458155","id":"PMC_18458155","title":"Kindlin-2 (Mig-2): a co-activator of beta3 integrins.","date":"2008","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18458155","citation_count":283,"is_preprint":false},{"pmid":"15620647","id":"PMC_15620647","title":"Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO.","date":"2004","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/15620647","citation_count":168,"is_preprint":false},{"pmid":"17513299","id":"PMC_17513299","title":"The MIG-2/integrin interaction strengthens cell-matrix adhesion and modulates cell motility.","date":"2007","source":"The Journal of biological 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Animal","url":"https://pubmed.ncbi.nlm.nih.gov/21614653","citation_count":11,"is_preprint":false},{"pmid":"38352691","id":"PMC_38352691","title":"Overexpression of FERM Domain Containing Kindlin 2 (FERMT2) in Fibroblasts Correlates with EMT and Immunosuppression in Gastric Cancer.","date":"2024","source":"International journal of genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38352691","citation_count":10,"is_preprint":false},{"pmid":"37357349","id":"PMC_37357349","title":"FERMT2 upregulation in CAFs enhances EMT of OSCC and M2 macrophage polarization.","date":"2023","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/37357349","citation_count":9,"is_preprint":false},{"pmid":"23288411","id":"PMC_23288411","title":"Differentiation of human ES cell line KIND-2 to yield tripotent cardiovascular progenitors.","date":"2013","source":"In vitro cellular & developmental biology. 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loss of migfilin impairs cell shape modulation.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, dominant-negative and loss-of-function experiments, live imaging of focal adhesion localization\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, domain mapping, loss-of-function with defined phenotype; foundational paper with 309 citations\",\n      \"pmids\": [\"12679033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Kindlin-2 (FERMT2/Mig-2) binds to the C-terminal region of integrin β3 cytoplasmic tail (TS752T region and NITY759 motif) via its PTB domain and functions as a co-activator of β3 integrins, synergizing with talin head domain to activate αIIbβ3; siRNA knockdown impairs talin-induced αIIbβ3 activation and αvβ3-mediated adhesion and migration.\",\n      \"method\": \"In vitro binding assays, co-transfection/co-activation assays in CHO cells, siRNA knockdown with flow cytometry readout of integrin activation, cell adhesion and migration assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding assay + mutagenesis of integrin tail + functional rescue; 283 citations, replicated across multiple cell types\",\n      \"pmids\": [\"18458155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FERMT2/Mig-2 interacts directly with β1 and β3 integrin cytoplasmic domains via a single site within its FERM domain; this interaction recruits Mig-2 to focal adhesions, promotes integrin activation, enhances cell-ECM adhesion, and reduces cell motility; an integrin-binding-defective mutant fails to rescue these functions.\",\n      \"method\": \"Pulldown assays with integrin cytoplasmic tail peptides, domain mutagenesis, αIIbβ3 activation assay in CHO cells, focal adhesion formation imaging, cell motility assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro binding with mutagenesis + multiple functional readouts; 148 citations\",\n      \"pmids\": [\"17513299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FERMT2 (a β3-integrin co-activator) modulates APP metabolism: FERMT2 underexpression increases mature APP levels at the cell surface by facilitating APP recycling, leading to increased Aβ peptide production.\",\n      \"method\": \"Genome-wide high-content siRNA screen, cell-surface APP quantification, APP recycling assays, CSF Aβ correlation in AD cases\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen followed by targeted validation with multiple readouts; single lab\",\n      \"pmids\": [\"27933404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FERMT2 loss in podocytes leads to altered cortical actin composition, plasma membrane blebbing, remodeling of focal adhesions, and elevated RhoA activation with increased actomyosin contractility; inhibition of actomyosin tension reverses the blebbing phenotype, establishing a direct link between FERMT2-mediated cell-matrix adhesion, cortical actin, and plasma membrane tension.\",\n      \"method\": \"Conditional genetic knockout (CRISPR/Cas9 in human podocytes and in vivo mouse models), RhoA activity assay, actomyosin inhibitor rescue, actin fractionation, focal adhesion imaging\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, multiple orthogonal assays, pharmacological rescue\",\n      \"pmids\": [\"29337051\"],\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 AD-risk allele rs7143400-T reduces FERMT2 expression via miR-4504 binding to the 3'UTR.\",\n      \"method\": \"Co-immunoprecipitation of FERMT2 and APP, genome-wide high-content screens, shRNA knockdown in neurons with axonal growth and LTP readouts, luciferase 3'UTR reporter assays for miR-4504\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein-protein interaction by Co-IP, functional rescue experiments, two independent genome-wide screens, miRNA mechanism validated by reporter assay\",\n      \"pmids\": [\"33144711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FERMT2 knockdown in human iPSC-derived neurons reduces extracellular Aβ levels and the proportion of phosphorylated TAU; CRISPR-Cas9 targeting of FERMT2 in familial AD neurons elevated Aβ42:40 ratio, demonstrating cell-type-specific and genetic-background-dependent effects on amyloid and tau proteostasis.\",\n      \"method\": \"shRNA lentiviral knockdown, CRISPR-Cas9 knockout in iPSC-derived neurons, ELISA for Aβ and phospho-tau\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/KD in human neurons with defined molecular readouts; single lab\",\n      \"pmids\": [\"30371777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mig-2/FERMT2 attenuates cisplatin-induced apoptosis in glioma cells through AKT/JNK and AKT/p38 signaling; the F3 subdomain of Mig-2 is necessary and sufficient for this anti-apoptotic effect, as shown by domain-deletion mutagenesis.\",\n      \"method\": \"Plasmid overexpression and siRNA knockdown, Annexin V/PI apoptosis assay, Western blotting of caspase and signaling proteins, kinase inhibitor pharmacology, F3-domain and deletion mutant transfection\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis combined with pharmacological pathway inhibition; single lab\",\n      \"pmids\": [\"25152024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FERMT2 is required for trophoblast-substrate adhesion and invasion; siRNA-mediated knockdown of FERMT2 in HTR8-SVneo cells significantly decreased cell-substrate attachment and invasive capacity, consistent with its role as an integrin activator in extravillous trophoblasts.\",\n      \"method\": \"siRNA knockdown, cell-substrate adhesion assay, invasion assay (Matrigel), immunofluorescence localization\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with two functional readouts; single lab, single method per assay\",\n      \"pmids\": [\"30382829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KINDLIN2/FERMT2 is a substrate of caspases and calpain I; these cleavages dissociate the F0 and F1 domains of KINDLIN2 and reduce its ability to control APP processing, representing a regulatory mechanism of KINDLIN2 function at the synapse relevant to AD pathophysiology.\",\n      \"method\": \"In vitro caspase and calpain cleavage assays, domain-dissociation analysis, APP processing assays after protease treatment\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical cleavage assay with domain mapping; single lab, single study\",\n      \"pmids\": [\"40273529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FERMT2 promotes anoikis resistance and peritoneal metastasis in gastric cancer by suppressing ubiquitination of SOX2 (stabilizing it), which upregulates FN1 transcription and drives fibronectin matrix deposition; TGFβ-1/TGFβ-RI signaling forms a positive feedback loop with FERMT2 to reinforce this mechanism.\",\n      \"method\": \"In vitro suspension assays, ubiquitination assays, ChIP/transcription reporter for FN1, in vivo peritoneal metastasis mouse models, TGFβ pathway inhibitors\",\n      \"journal\": \"Gastric cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway defined by ubiquitination assay + transcriptional readout + in vivo validation; single lab\",\n      \"pmids\": [\"40024947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FERMT2 is required for YAP/TAZ nuclear accumulation, YAP/TAZ target gene expression, and phosphorylation at key tyrosine residues in breast cancer cells; mechanistically, 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; partial epistasis also indicates actin-dependent regulation of YAP/TAZ by FERMT2.\",\n      \"method\": \"CRISPR/Cas9 loss-of-function screens (in vitro and in vivo), FERMT2 knockout and silencing, YAP/TAZ nuclear localization assay, phospho-FAK western blotting, FAK activator rescue, epistasis analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR screen + targeted KO + pathway epistasis + pharmacological rescue; multiple orthogonal methods in single study\",\n      \"pmids\": [\"41792242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FERMT2 promotes colorectal carcinoma progression via the Wnt/β-catenin signaling pathway; overexpression of FERMT2 upregulates Wnt/β-catenin components, while FERMT2 knockdown suppresses migration, invasion, and EMT, effects that are rescued by β-catenin overexpression.\",\n      \"method\": \"FERMT2 overexpression and siRNA knockdown, Western blotting for Wnt/β-catenin proteins, migration/invasion assays, β-catenin rescue experiment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis by rescue experiment; single lab\",\n      \"pmids\": [\"36480537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FERMT2 maintains the myofibroblastic phenotype of gastric cancer-associated fibroblasts by acting as a ceRNA for ZEB2, promoting α-SMA transcription; FERMT2 also drives GCAF-derived TGF-β1 secretion, and tumor-derived FERMT2 upregulates COL6A1 which is transferred to GCAFs via exosomes to amplify TGF-β signaling in a positive feedback loop.\",\n      \"method\": \"ceRNA/luciferase reporter assays, α-SMA transcription analysis, ELISA for TGF-β1, exosome isolation and transfer assays, co-culture functional assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple molecular mechanisms tested with orthogonal methods; single lab\",\n      \"pmids\": [\"41079932\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FERMT2/Kindlin-2 is a FERM domain-containing focal adhesion scaffold protein that co-activates β1 and β3 integrins by binding their cytoplasmic tails, links cell-matrix adhesions to the actin cytoskeleton (via filamin and migfilin interactions), modulates RhoA/actomyosin contractility and plasma membrane tension, activates YAP/TAZ through integrin-FAK signaling, directly interacts with APP to regulate its surface trafficking and Aβ production (with its function further tuned by caspase/calpain cleavage of its F0-F1 domains), and promotes cancer progression through Wnt/β-catenin, TGFβ, and SOX2-FN1 axes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FERMT2 (Kindlin-2) is a FERM domain-containing focal adhesion protein that co-activates β1 and β3 integrins, couples integrin-mediated adhesion to the actin cytoskeleton, and transduces mechanical and signaling cues to downstream effector pathways including RhoA/actomyosin, FAK–YAP/TAZ, Wnt/β-catenin, and TGFβ signaling. FERMT2 binds integrin β-subunit cytoplasmic tails through its PTB/FERM domain, synergizes with talin to drive integrin activation, and connects to the actin cytoskeleton via interactions with migfilin and filamin; loss of FERMT2 causes aberrant RhoA activation, membrane blebbing, and impaired adhesion and migration [PMID:12679033, PMID:18458155, PMID:17513299, PMID:29337051]. FERMT2 directly interacts with APP to regulate its surface trafficking and Aβ production, and caspase/calpain-mediated cleavage of its F0–F1 domains modulates this activity, linking FERMT2 to Alzheimer's disease-associated amyloid and tau proteostasis [PMID:33144711, PMID:40273529, PMID:30371777]. In cancer contexts, FERMT2 activates YAP/TAZ nuclear accumulation through integrin–FAK signaling independently of canonical Hippo kinases, stabilizes SOX2 to upregulate fibronectin and promote anoikis resistance, and drives Wnt/β-catenin-dependent epithelial–mesenchymal transition [PMID:41792242, PMID:40024947, PMID:36480537].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying FERMT2's first interacting partners established that focal adhesion scaffolding — rather than enzymatic activity — is its primary molecular role, answering how cell-matrix adhesions connect to the actin cytoskeleton through the migfilin–filamin axis.\",\n      \"evidence\": \"Co-immunoprecipitation, pulldown assays, and dominant-negative experiments in cultured cells showing migfilin bridges FERMT2 to filamin and actin\",\n      \"pmids\": [\"12679033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Integrin-binding mechanism of FERMT2 not yet characterized\",\n        \"Whether FERMT2 directly activates integrins or only scaffolds was unknown\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping FERMT2's FERM domain as the direct binding interface for β1 and β3 integrin cytoplasmic tails resolved how FERMT2 is recruited to focal adhesions and demonstrated that this interaction promotes integrin activation and cell-ECM adhesion.\",\n      \"evidence\": \"Pulldown assays with integrin tail peptides, domain mutagenesis, αIIbβ3 activation in CHO cells, focal adhesion imaging\",\n      \"pmids\": [\"17513299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether FERMT2 synergizes with talin for integrin activation was not addressed\",\n        \"Structural basis of the FERM–integrin tail interaction at atomic resolution was lacking\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that FERMT2 synergizes with talin head domain to co-activate αIIbβ3 and that its PTB domain recognizes specific motifs (NITY759) in the β3 tail established the talin–kindlin cooperativity model of inside-out integrin signaling.\",\n      \"evidence\": \"In vitro binding assays, co-transfection of talin head + FERMT2 in CHO cells, siRNA knockdown with flow cytometry integrin activation readout\",\n      \"pmids\": [\"18458155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How FERMT2 and talin simultaneously engage the same integrin tail sterically was unresolved\",\n        \"Relevance to β1-integrin co-activation in non-hematopoietic cells not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying the F3 subdomain as necessary and sufficient for AKT/JNK-dependent anti-apoptotic signaling revealed that FERMT2 has signaling functions beyond mechanical adhesion scaffolding.\",\n      \"evidence\": \"Overexpression/siRNA in glioma cells, domain-deletion mutagenesis, kinase inhibitor pharmacology, apoptosis assays\",\n      \"pmids\": [\"25152024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding partner for F3 in the AKT pathway not identified\",\n        \"Whether this anti-apoptotic function is integrin-dependent was not determined\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A genome-wide siRNA screen uncovered an unexpected role for FERMT2 in APP metabolism, showing that FERMT2 underexpression increases cell-surface mature APP and Aβ production — the first link between FERMT2 and Alzheimer's disease biology.\",\n      \"evidence\": \"High-content siRNA screen, cell-surface APP quantification, APP recycling assays, CSF Aβ correlation\",\n      \"pmids\": [\"27933404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether FERMT2 directly binds APP or acts indirectly through integrins was unknown\",\n        \"Mechanism of APP recycling regulation by FERMT2 not defined\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"FERMT2 loss in podocytes was shown to elevate RhoA activation and actomyosin contractility, causing membrane blebbing reversible by actomyosin inhibition — establishing FERMT2 as a negative regulator of RhoA-dependent cortical tension downstream of integrin adhesion.\",\n      \"evidence\": \"CRISPR KO in human podocytes and conditional mouse KO, RhoA activity assay, pharmacological rescue with actomyosin inhibitors\",\n      \"pmids\": [\"29337051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the RhoGEF or RhoGAP regulated by FERMT2 not determined\",\n        \"Whether this mechanism operates in cell types beyond podocytes was untested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Validation in iPSC-derived neurons showed that FERMT2 modulates both Aβ and phospho-tau levels, but with direction depending on genetic background (knockdown reduces Aβ in wild-type neurons; CRISPR KO in familial AD neurons elevates Aβ42:40 ratio), highlighting context-dependent effects.\",\n      \"evidence\": \"shRNA and CRISPR-Cas9 in iPSC-derived neurons, ELISA for Aβ species and phospho-tau\",\n      \"pmids\": [\"30371777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism underlying opposing effects in different genetic backgrounds not resolved\",\n        \"Whether tau phosphorylation is a direct or indirect consequence of FERMT2 loss unclear\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating direct FERMT2–APP protein interaction by Co-IP, and showing that FERMT2 underexpression impairs axonal growth, synaptic connectivity, and LTP in an APP-dependent manner, established FERMT2 as a direct regulator of APP function in neurons; the AD-risk SNP rs7143400-T was shown to reduce FERMT2 expression via miR-4504.\",\n      \"evidence\": \"Co-immunoprecipitation, genome-wide screens, shRNA in neurons with axonal/LTP readouts, luciferase 3'UTR reporter for miR-4504\",\n      \"pmids\": [\"33144711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Binding interface between FERMT2 and APP not mapped at domain level\",\n        \"Whether integrin co-activation is required for the FERMT2–APP interaction not tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Epistasis experiments in colorectal carcinoma cells showed that FERMT2 drives migration, invasion, and EMT through the Wnt/β-catenin pathway, with β-catenin overexpression rescuing FERMT2-knockdown phenotypes — establishing a second oncogenic signaling axis for FERMT2.\",\n      \"evidence\": \"FERMT2 overexpression/knockdown, Wnt/β-catenin western blotting, β-catenin rescue of migration and invasion\",\n      \"pmids\": [\"36480537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether FERMT2 regulates β-catenin via integrin-dependent or integrin-independent mechanism unknown\",\n        \"Direct molecular link between FERMT2 and β-catenin stabilization not identified\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Caspase and calpain I were identified as proteases that cleave FERMT2 between its F0 and F1 domains, reducing its control of APP processing — revealing a post-translational regulatory mechanism relevant to neurodegeneration.\",\n      \"evidence\": \"In vitro caspase/calpain cleavage assays, domain-dissociation analysis, APP processing readouts\",\n      \"pmids\": [\"40273529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo relevance of FERMT2 cleavage at the synapse not demonstrated\",\n        \"Cleavage site residues not precisely mapped\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In gastric cancer, FERMT2 was shown to stabilize SOX2 by suppressing its ubiquitination, leading to FN1 transcriptional upregulation and anoikis resistance, with TGFβ-1/TGFβ-RI forming a positive feedback loop — defining a complete FERMT2–SOX2–FN1–TGFβ signaling circuit for peritoneal metastasis.\",\n      \"evidence\": \"Ubiquitination assays, ChIP/reporter for FN1, in vivo peritoneal metastasis models, TGFβ inhibitor experiments\",\n      \"pmids\": [\"40024947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether FERMT2 directly binds SOX2 or acts through an E3 ligase intermediate not resolved\",\n        \"Generalizability to cancers beyond gastric not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"FERMT2 was shown to activate YAP/TAZ nuclear accumulation through integrin–FAK signaling independently of canonical Hippo kinases LATS1/2, with glucocorticoid-driven FAK activation rescuing YAP/TAZ in FERMT2-depleted cells — establishing a Hippo-independent mechanotransduction pathway in breast cancer.\",\n      \"evidence\": \"CRISPR screen (in vitro and in vivo), FERMT2 KO, phospho-FAK blotting, FAK activator rescue, epistasis analysis\",\n      \"pmids\": [\"41792242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How FAK phosphorylation leads to YAP tyrosine phosphorylation at specific residues not mapped\",\n        \"Whether this Hippo-independent YAP regulation applies to non-malignant cells not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of simultaneous FERMT2–talin–integrin engagement, the direct binding interface between FERMT2 and APP, the identity of RhoGEFs/GAPs linking FERMT2 to RhoA, and whether FERMT2's diverse signaling outputs (Wnt, TGFβ, YAP/TAZ) are all integrin-dependent or reflect integrin-independent scaffolding functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of FERMT2 in complex with integrin tail and talin\",\n        \"Binding interface between FERMT2 and APP not mapped\",\n        \"Whether Wnt/β-catenin and SOX2 stabilization functions require integrin binding unknown\"\n      ]\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, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 11, 12]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 12, 13]}\n    ],\n    \"complexes\": [\n      \"Integrin-kindlin-talin adhesion complex\"\n    ],\n    \"partners\": [\n      \"ITGB3\",\n      \"ITGB1\",\n      \"TLN1\",\n      \"FLNA\",\n      \"FBLIM1\",\n      \"APP\",\n      \"SOX2\",\n      \"PTK2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}