{"gene":"FARP2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2005,"finding":"FARP2 directly associates with plexin-A1 in the presence of neuropilin-1. Sema3A binding to neuropilin-1 induces dissociation of FARP2 from plexin-A1, resulting in activation of FARP2's Rac GEF activity, Rnd1 recruitment to plexin-A1, and downregulation of R-Ras. Simultaneously, the FERM domain of FARP2 sequesters PIPKIgamma661 from talin, inhibiting its kinase activity. Both activities are required for Sema3A-mediated axonal repulsion and suppression of neuronal adhesion.","method":"Co-immunoprecipitation, GEF activity assays, biochemical dissociation assays, functional axon repulsion assays","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, biochemical GEF assays, and functional cellular readouts in a single focused study; widely replicated concept","pmids":["16286926"],"is_preprint":false},{"year":2004,"finding":"FRG (FARP2) functions as a GDP/GTP exchange factor specific for Cdc42. At nectin-based cell-cell adhesion sites, nectins recruit and activate c-Src, which then recruits FRG, tyrosine phosphorylates it, and activates it, leading to local Cdc42 activation and adherens junction formation. RNAi depletion of FRG suppressed nectin-induced Cdc42 activation.","method":"Co-immunoprecipitation, RNAi knockdown, GEF activity assay, tyrosine phosphorylation assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi, and biochemical GEF assay with functional adherens junction readout","pmids":["15277544"],"is_preprint":false},{"year":2006,"finding":"FRG (FARP2), alongside Vav2, mediates CD47-induced activation of Cdc42 and Rac in hippocampal neurons downstream of Src, promoting dendrite and axon development. Inhibition of FRG prevented CD47-promoted dendritic development.","method":"Inhibition of FRG (dominant negative/pharmacological), overexpression of CD47, autophosphorylation assays, morphological analysis of hippocampal neurons","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional inhibition with defined cellular phenotype in neurons, single lab","pmids":["17135401"],"is_preprint":false},{"year":2010,"finding":"FARP2 is required for localized activation of Rac1 (GTP-bound form) into podosome-ring-like structures in osteoclasts, and is relevant to integrin β3 activity during osteoclastogenesis. FARP2 deficiency reduces formation of multinucleated osteoclasts and resorption pits.","method":"Live cell imaging, biochemical GTP-Rac1 pull-down assays, FARP2 knockdown/knockout osteoclasts, functional resorption pit assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live imaging, biochemical GEF assays, and loss-of-function with multiple cellular readouts in a single focused study","pmids":["20702777"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of the DH and DH-PH-PH domains of FARP2 reveal an autoinhibited conformation in which the GEF substrate-binding site is blocked collectively by the last helix of the DH domain and the two PH domains, stabilized by multiple inter-domain interactions. Cell-based activity assays confirmed suppression of FARP2 GEF activity by these autoinhibitory elements.","method":"X-ray crystallography, cell-based GEF activity assays","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by cell-based assays, rigorous structural and biochemical methods","pmids":["23375260"],"is_preprint":false},{"year":2019,"finding":"FARP2 is a RIPR motif-dependent binding partner and phosphorylation substrate of aPKCι. The interaction is mediated by a FERM/FA domain–kinase domain interface, and aPKCι-dependent phosphorylation promotes detachment of FARP2. FARP2 promotes GTP loading of Cdc42, consistent with upstream regulation of the PAR6-aPKCι polarity complex. aPKCι-mediated phosphorylation of FARP2 acts as a positive feedback loop to drive polarisation and tight junction formation.","method":"Co-immunoprecipitation, phosphorylation assay, siRNA knockdown, GTP-Cdc42 pull-down, cell polarity and junction formation assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding, phosphorylation substrate assay, knockdown with junction formation readout, multiple orthogonal methods in single study","pmids":["30872454"],"is_preprint":false},{"year":2020,"finding":"FARP2 binds to the KRK motif in the PlxnA4 cytoplasmic domain and mediates Sema3A-induced Rac1 activation specifically for dendritic elaboration of cortical neurons, but is dispensable for Sema3A-mediated axon growth cone collapse. This defines a Sema3A-Nrp1/PlxnA4/FARP2/Rac1 pathway selectively controlling dendrite morphogenesis.","method":"CRISPR/Cas9 knock-in mice (KRK motif mutation), FARP2 loss-of-function, Rac1 activity assays, dendritic morphology and axon guidance assays in vivo and in vitro","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR knock-in genetic epistasis, FARP2 loss-of-function, Rac1 activity measurement, in vivo and in vitro complementary readouts","pmids":["32499377"],"is_preprint":false},{"year":2026,"finding":"TGF-β1 upregulates FARP2 expression in corneal stromal fibroblasts; FARP2 knockdown suppresses TGF-β1-induced upregulation of RHOA, TLN1, SLC2A4, and COL1A1, reduces α-SMA expression (myofibroblast marker), and markedly reduces cell migration in scratch assay, indicating FARP2 is required for TGF-β1-mediated myofibroblast differentiation and corneal fibrosis.","method":"siRNA knockdown, real-time PCR, Western blotting, immunocytochemistry (α-SMA), scratch/wound healing assay","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA knockdown with multiple gene expression readouts and functional migration assay, single lab, no in vivo confirmation","pmids":["41786192"],"is_preprint":false}],"current_model":"FARP2 is a FERM domain-containing Dbl-family guanine nucleotide exchange factor (GEF) that activates Rac1 and Cdc42 downstream of multiple upstream signals: it basally associates with plexin-A1 in an autoinhibited state (structurally characterized by crystal structures showing DH and PH domain-mediated autoinhibition), is released and activated upon Sema3A/neuropilin-1 engagement to mediate axonal repulsion and, via a distinct PlxnA4 KRK motif-dependent pathway, dendritic morphogenesis through Rac1; it is tyrosine-phosphorylated and activated by c-Src downstream of nectin trans-interactions to locally activate Cdc42 at adherens junctions; it is phosphorylated by aPKCι to form a positive feedback loop driving epithelial polarity and tight junction formation; and it activates Rac1 in osteoclast podosomes to regulate bone resorption, with additional roles in TGF-β1-mediated myofibroblast differentiation."},"narrative":{"mechanistic_narrative":"FARP2 (FRG) is a FERM domain-containing Dbl-family guanine nucleotide exchange factor for the Rho GTPases Rac1 and Cdc42 that converts multiple cell-surface signals into localized cytoskeletal remodeling [PMID:16286926, PMID:15277544]. Its GEF activity is intrinsically held off: crystal structures of the DH and DH-PH-PH module show an autoinhibited conformation in which the substrate-binding site is occluded by the terminal DH helix and the two PH domains, and disrupting these elements relieves suppression in cells [PMID:23375260]. This autoinhibited pool is recruited to signaling platforms and released by defined upstream cues. In semaphorin signaling, FARP2 basally associates with plexin-A1; Sema3A binding to neuropilin-1 triggers FARP2 dissociation, activating its Rac GEF activity, promoting Rnd1 recruitment and R-Ras downregulation, while its FERM domain sequesters PIPKIgamma661 from talin to drive axonal repulsion [PMID:16286926]. Through a distinct interaction with the KRK motif of PlxnA4, FARP2 mediates Sema3A-induced Rac1 activation selectively for dendritic morphogenesis [PMID:32499377]. At nectin-based adherens junctions, c-Src recruits and tyrosine-phosphorylates FARP2 to locally activate Cdc42 [PMID:15277544], and aPKCι binds and phosphorylates FARP2 to form a positive-feedback loop driving epithelial polarity and tight junction formation [PMID:30872454]. Beyond neurons and epithelia, FARP2 supports localized Rac1 activation in osteoclast podosomes during bone resorption [PMID:20702777] and is required for TGF-β1-driven myofibroblast differentiation [PMID:41786192].","teleology":[{"year":2004,"claim":"Established FARP2 as a Cdc42-specific GEF that is recruited and activated at cell-cell adhesion sites, linking nectin/Src signaling to junction assembly.","evidence":"Co-IP, RNAi, GEF and tyrosine-phosphorylation assays at nectin-based junctions","pmids":["15277544"],"confidence":"High","gaps":["Did not resolve how Src-mediated phosphorylation structurally relieves autoinhibition","Selectivity between Cdc42 and Rac in this context not fully defined"]},{"year":2005,"claim":"Defined FARP2 as the Rac GEF released from plexin-A1 upon Sema3A/neuropilin-1 engagement, coupling a guidance receptor to bifunctional Rac activation and talin/PIPKIgamma sequestration in axon repulsion.","evidence":"Reciprocal Co-IP, biochemical dissociation and GEF assays, axon repulsion functional readouts","pmids":["16286926"],"confidence":"High","gaps":["Mechanism triggering dissociation from plexin-A1 at atomic resolution unknown","Relative contribution of GEF activity versus PIPKIgamma sequestration not quantified"]},{"year":2006,"claim":"Placed FARP2 downstream of CD47/Src as a contributor to Cdc42/Rac activation supporting neuronal process development.","evidence":"FRG inhibition, CD47 overexpression, autophosphorylation assays and neuronal morphology in hippocampal neurons","pmids":["17135401"],"confidence":"Medium","gaps":["Relied on inhibition rather than clean loss-of-function","Functional redundancy with Vav2 not dissected","Single lab"]},{"year":2010,"claim":"Extended FARP2's role beyond neurons by showing it drives localized Rac1 activation in osteoclast podosomes required for resorption and osteoclastogenesis.","evidence":"Live imaging, GTP-Rac1 pull-down, knockdown/knockout osteoclasts, resorption pit assay","pmids":["20702777"],"confidence":"High","gaps":["Upstream receptor recruiting FARP2 to podosomes not identified","Link to integrin β3 activation mechanistically incomplete"]},{"year":2013,"claim":"Provided the structural basis for FARP2 regulation, showing intramolecular autoinhibition of the GEF active site by the DH and tandem PH domains.","evidence":"X-ray crystallography of DH and DH-PH-PH modules with cell-based GEF activity validation","pmids":["23375260"],"confidence":"High","gaps":["Structure of the activated, signal-released state not determined","How phosphorylation or receptor binding triggers the conformational switch unresolved"]},{"year":2019,"claim":"Identified FARP2 as an aPKCι binding partner and phosphorylation substrate forming a positive-feedback loop that activates Cdc42 to drive epithelial polarity and tight junction formation.","evidence":"Co-IP, phosphorylation assay, siRNA, GTP-Cdc42 pull-down, polarity and junction assays","pmids":["30872454"],"confidence":"High","gaps":["How phosphorylation-induced detachment couples to Cdc42 loading not structurally defined","In vivo relevance of the feedback loop not tested"]},{"year":2020,"claim":"Resolved pathway specificity by showing FARP2 binds the PlxnA4 KRK motif to mediate Sema3A-induced Rac1 activation for dendrite morphogenesis while being dispensable for axon growth cone collapse.","evidence":"CRISPR/Cas9 KRK knock-in mice, FARP2 loss-of-function, Rac1 activity assays, dendritic and axon guidance readouts in vivo and in vitro","pmids":["32499377"],"confidence":"High","gaps":["What distinguishes the plexin-A1 versus PlxnA4 FARP2 pools mechanistically unclear","Effector specificity for dendrite versus axon outcomes not fully explained"]},{"year":2026,"claim":"Implicated FARP2 in pathological tissue remodeling, showing it is induced by TGF-β1 and required for myofibroblast differentiation and migration in corneal stromal fibroblasts.","evidence":"siRNA knockdown, qPCR, Western blot, α-SMA immunocytochemistry, scratch migration assay","pmids":["41786192"],"confidence":"Medium","gaps":["No in vivo confirmation of a role in corneal fibrosis","GTPase effector mediating the fibrotic phenotype not directly demonstrated","Single lab"]},{"year":null,"claim":"How the structurally defined autoinhibited state is converted to the active state by the diverse upstream inputs (plexin release, Src and aPKCι phosphorylation) remains unresolved at the mechanistic level.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of an activated/receptor-bound FARP2 state","Quantitative rules for Rac1 versus Cdc42 selectivity across contexts undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,5]}],"complexes":[],"partners":["PLXNA1","NRP1","PLXNA4","PRKCI","SRC","PIP5K1C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94887","full_name":"FERM, ARHGEF and pleckstrin domain-containing protein 2","aliases":["FERM domain-including RhoGEF","FIR","FERM, RhoGEF and pleckstrin domain-containing protein 2","Pleckstrin homology domain-containing family C member 3","PH domain-containing family C member 3"],"length_aa":1054,"mass_kda":119.9,"function":"Functions as a guanine nucleotide exchange factor that activates RAC1. May have relatively low activity. Plays a role in the response to class 3 semaphorins and remodeling of the actin cytoskeleton. Plays a role in TNFSF11-mediated osteoclast differentiation, especially in podosome rearrangement and reorganization of the actin cytoskeleton. Regulates the activation of ITGB3, integrin signaling and cell adhesion (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O94887/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FARP2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CLNS1A","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FARP2","total_profiled":1310},"omim":[{"mim_id":"617586","title":"FERM, ARHGEF, AND PLECKSTRIN DOMAINS-CONTAINING PROTEIN 2; FARP2","url":"https://www.omim.org/entry/617586"},{"mim_id":"300628","title":"FERM DOMAIN-CONTAINING PROTEIN 7; FRMD7","url":"https://www.omim.org/entry/300628"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FARP2"},"hgnc":{"alias_symbol":["KIAA0793","FIR","PLEKHC3","FRG"],"prev_symbol":[]},"alphafold":{"accession":"O94887","domains":[{"cath_id":"3.10.20.90","chopping":"45-122","consensus_level":"medium","plddt":88.3094,"start":45,"end":122},{"cath_id":"2.30.29.30","chopping":"233-328_341-347","consensus_level":"medium","plddt":86.479,"start":233,"end":347},{"cath_id":"1.20.900.10","chopping":"536-741","consensus_level":"high","plddt":93.4779,"start":536,"end":741},{"cath_id":"2.30.29.30","chopping":"752-857","consensus_level":"high","plddt":89.3089,"start":752,"end":857},{"cath_id":"2.30.29.30","chopping":"932-1026","consensus_level":"high","plddt":92.5536,"start":932,"end":1026}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94887","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94887-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94887-F1-predicted_aligned_error_v6.png","plddt_mean":74.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FARP2","jax_strain_url":"https://www.jax.org/strain/search?query=FARP2"},"sequence":{"accession":"O94887","fasta_url":"https://rest.uniprot.org/uniprotkb/O94887.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94887/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94887"}},"corpus_meta":[{"pmid":"16286926","id":"PMC_16286926","title":"FARP2 triggers signals for Sema3A-mediated axonal repulsion.","date":"2005","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16286926","citation_count":186,"is_preprint":false},{"pmid":"15277544","id":"PMC_15277544","title":"Activation of Cdc42 by trans interactions of the cell adhesion molecules nectins through c-Src and Cdc42-GEF FRG.","date":"2004","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15277544","citation_count":91,"is_preprint":false},{"pmid":"1629179","id":"PMC_1629179","title":"mRNP4, a major mRNA-binding protein from Xenopus oocytes is identical to transcription factor FRG Y2.","date":"1992","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1629179","citation_count":82,"is_preprint":false},{"pmid":"17135401","id":"PMC_17135401","title":"CD47 promotes neuronal development through Src- and FRG/Vav2-mediated activation of Rac and Cdc42.","date":"2006","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17135401","citation_count":68,"is_preprint":false},{"pmid":"7563973","id":"PMC_7563973","title":"Gastroprotective activity of FRG-8813, a novel histamine H2-receptor antagonist, in rats.","date":"1995","source":"Japanese journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/7563973","citation_count":67,"is_preprint":false},{"pmid":"8099553","id":"PMC_8099553","title":"Gastric antisecretory effect of FRG-8813, a new histamine H2 receptor antagonist, in rats and dogs.","date":"1993","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/8099553","citation_count":54,"is_preprint":false},{"pmid":"29129708","id":"PMC_29129708","title":"Efficacy of hepatitis B virus ribonuclease H inhibitors, a new class of replication antagonists, in FRG human liver chimeric mice.","date":"2017","source":"Antiviral research","url":"https://pubmed.ncbi.nlm.nih.gov/29129708","citation_count":35,"is_preprint":false},{"pmid":"19365831","id":"PMC_19365831","title":"FARP2, HDLBP and PASK are downregulated in a patient with autism and 2q37.3 deletion syndrome.","date":"2009","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/19365831","citation_count":34,"is_preprint":false},{"pmid":"20702777","id":"PMC_20702777","title":"Integral roles of a guanine nucleotide exchange factor, FARP2, in osteoclast podosome rearrangements.","date":"2010","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/20702777","citation_count":34,"is_preprint":false},{"pmid":"23375260","id":"PMC_23375260","title":"Structural basis for autoinhibition of the guanine nucleotide exchange factor FARP2.","date":"2013","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/23375260","citation_count":32,"is_preprint":false},{"pmid":"20215405","id":"PMC_20215405","title":"Facioscapulohumeral muscular dystrophy region gene-1 (FRG-1) is an actin-bundling protein associated with muscle-attachment sites.","date":"2010","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/20215405","citation_count":32,"is_preprint":false},{"pmid":"32499377","id":"PMC_32499377","title":"Modular and Distinct Plexin-A4/FARP2/Rac1 Signaling Controls Dendrite Morphogenesis.","date":"2020","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32499377","citation_count":31,"is_preprint":false},{"pmid":"38782768","id":"PMC_38782768","title":"Identifying novel mechanisms of per- and polyfluoroalkyl substance-induced hepatotoxicity using FRG humanized mice.","date":"2024","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38782768","citation_count":17,"is_preprint":false},{"pmid":"6663246","id":"PMC_6663246","title":"Creatine kinase variants. 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A contribution to the improvement of medical care to children of migrant labourers in the FRG (author's transl)].","date":"1982","source":"Klinische Padiatrie","url":"https://pubmed.ncbi.nlm.nih.gov/7062688","citation_count":4,"is_preprint":false},{"pmid":"37350098","id":"PMC_37350098","title":"Recapitulation of Skewed X-Inactivation in Female Ornithine Transcarbamylase-Deficient Primary Human Hepatocytes in the FRG Mouse: A Novel System for Developing Epigenetic Therapies.","date":"2023","source":"Human gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37350098","citation_count":3,"is_preprint":false},{"pmid":"4007161","id":"PMC_4007161","title":"Optical properties and structure of tetrapyrroles. A report of a symposium held at the University of Konstanz, FRG, August 12-17, 1984.","date":"1985","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/4007161","citation_count":2,"is_preprint":false},{"pmid":"7829023","id":"PMC_7829023","title":"[Effects of FRG-8813, a new histamine H2-receptor antagonist, on gastric mucus in rats].","date":"1994","source":"Nihon yakurigaku zasshi. Folia pharmacologica Japonica","url":"https://pubmed.ncbi.nlm.nih.gov/7829023","citation_count":1,"is_preprint":false},{"pmid":"41786192","id":"PMC_41786192","title":"Pivotal role of FARP2 in TGF-β1-mediated myofibroblast differentiation and corneal fibrosis.","date":"2026","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41786192","citation_count":0,"is_preprint":false},{"pmid":"28976655","id":"PMC_28976655","title":"The novel histamine H2 receptor antagonist FRG-8813 prevents delay of wound repair induced by hydrogen peroxide in a rabbit gastric epithelial cell system.","date":"1998","source":"Journal of gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/28976655","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.14.25337714","title":"Suicide mortality in eastern and western Germany: construction of consistent time series 1952 to 2022","date":"2025-10-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.14.25337714","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.27.615529","title":"<i>Plasmodium falciparum</i>  quinine resistance is multifactorial and includes a role for the drug/metabolite transporters PfCRT and DMT1","date":"2024-09-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.27.615529","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21563,"output_tokens":2378,"usd":0.05018,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9385,"output_tokens":2985,"usd":0.060775,"stage2_stop_reason":"end_turn"},"total_usd":0.110955,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"FARP2 directly associates with plexin-A1 in the presence of neuropilin-1. Sema3A binding to neuropilin-1 induces dissociation of FARP2 from plexin-A1, resulting in activation of FARP2's Rac GEF activity, Rnd1 recruitment to plexin-A1, and downregulation of R-Ras. Simultaneously, the FERM domain of FARP2 sequesters PIPKIgamma661 from talin, inhibiting its kinase activity. Both activities are required for Sema3A-mediated axonal repulsion and suppression of neuronal adhesion.\",\n      \"method\": \"Co-immunoprecipitation, GEF activity assays, biochemical dissociation assays, functional axon repulsion assays\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, biochemical GEF assays, and functional cellular readouts in a single focused study; widely replicated concept\",\n      \"pmids\": [\"16286926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"FRG (FARP2) functions as a GDP/GTP exchange factor specific for Cdc42. At nectin-based cell-cell adhesion sites, nectins recruit and activate c-Src, which then recruits FRG, tyrosine phosphorylates it, and activates it, leading to local Cdc42 activation and adherens junction formation. RNAi depletion of FRG suppressed nectin-induced Cdc42 activation.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, GEF activity assay, tyrosine phosphorylation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi, and biochemical GEF assay with functional adherens junction readout\",\n      \"pmids\": [\"15277544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FRG (FARP2), alongside Vav2, mediates CD47-induced activation of Cdc42 and Rac in hippocampal neurons downstream of Src, promoting dendrite and axon development. Inhibition of FRG prevented CD47-promoted dendritic development.\",\n      \"method\": \"Inhibition of FRG (dominant negative/pharmacological), overexpression of CD47, autophosphorylation assays, morphological analysis of hippocampal neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional inhibition with defined cellular phenotype in neurons, single lab\",\n      \"pmids\": [\"17135401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FARP2 is required for localized activation of Rac1 (GTP-bound form) into podosome-ring-like structures in osteoclasts, and is relevant to integrin β3 activity during osteoclastogenesis. FARP2 deficiency reduces formation of multinucleated osteoclasts and resorption pits.\",\n      \"method\": \"Live cell imaging, biochemical GTP-Rac1 pull-down assays, FARP2 knockdown/knockout osteoclasts, functional resorption pit assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging, biochemical GEF assays, and loss-of-function with multiple cellular readouts in a single focused study\",\n      \"pmids\": [\"20702777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of the DH and DH-PH-PH domains of FARP2 reveal an autoinhibited conformation in which the GEF substrate-binding site is blocked collectively by the last helix of the DH domain and the two PH domains, stabilized by multiple inter-domain interactions. Cell-based activity assays confirmed suppression of FARP2 GEF activity by these autoinhibitory elements.\",\n      \"method\": \"X-ray crystallography, cell-based GEF activity assays\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by cell-based assays, rigorous structural and biochemical methods\",\n      \"pmids\": [\"23375260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FARP2 is a RIPR motif-dependent binding partner and phosphorylation substrate of aPKCι. The interaction is mediated by a FERM/FA domain–kinase domain interface, and aPKCι-dependent phosphorylation promotes detachment of FARP2. FARP2 promotes GTP loading of Cdc42, consistent with upstream regulation of the PAR6-aPKCι polarity complex. aPKCι-mediated phosphorylation of FARP2 acts as a positive feedback loop to drive polarisation and tight junction formation.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, siRNA knockdown, GTP-Cdc42 pull-down, cell polarity and junction formation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding, phosphorylation substrate assay, knockdown with junction formation readout, multiple orthogonal methods in single study\",\n      \"pmids\": [\"30872454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FARP2 binds to the KRK motif in the PlxnA4 cytoplasmic domain and mediates Sema3A-induced Rac1 activation specifically for dendritic elaboration of cortical neurons, but is dispensable for Sema3A-mediated axon growth cone collapse. This defines a Sema3A-Nrp1/PlxnA4/FARP2/Rac1 pathway selectively controlling dendrite morphogenesis.\",\n      \"method\": \"CRISPR/Cas9 knock-in mice (KRK motif mutation), FARP2 loss-of-function, Rac1 activity assays, dendritic morphology and axon guidance assays in vivo and in vitro\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR knock-in genetic epistasis, FARP2 loss-of-function, Rac1 activity measurement, in vivo and in vitro complementary readouts\",\n      \"pmids\": [\"32499377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TGF-β1 upregulates FARP2 expression in corneal stromal fibroblasts; FARP2 knockdown suppresses TGF-β1-induced upregulation of RHOA, TLN1, SLC2A4, and COL1A1, reduces α-SMA expression (myofibroblast marker), and markedly reduces cell migration in scratch assay, indicating FARP2 is required for TGF-β1-mediated myofibroblast differentiation and corneal fibrosis.\",\n      \"method\": \"siRNA knockdown, real-time PCR, Western blotting, immunocytochemistry (α-SMA), scratch/wound healing assay\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA knockdown with multiple gene expression readouts and functional migration assay, single lab, no in vivo confirmation\",\n      \"pmids\": [\"41786192\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FARP2 is a FERM domain-containing Dbl-family guanine nucleotide exchange factor (GEF) that activates Rac1 and Cdc42 downstream of multiple upstream signals: it basally associates with plexin-A1 in an autoinhibited state (structurally characterized by crystal structures showing DH and PH domain-mediated autoinhibition), is released and activated upon Sema3A/neuropilin-1 engagement to mediate axonal repulsion and, via a distinct PlxnA4 KRK motif-dependent pathway, dendritic morphogenesis through Rac1; it is tyrosine-phosphorylated and activated by c-Src downstream of nectin trans-interactions to locally activate Cdc42 at adherens junctions; it is phosphorylated by aPKCι to form a positive feedback loop driving epithelial polarity and tight junction formation; and it activates Rac1 in osteoclast podosomes to regulate bone resorption, with additional roles in TGF-β1-mediated myofibroblast differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FARP2 (FRG) is a FERM domain-containing Dbl-family guanine nucleotide exchange factor for the Rho GTPases Rac1 and Cdc42 that converts multiple cell-surface signals into localized cytoskeletal remodeling [#0, #1]. Its GEF activity is intrinsically held off: crystal structures of the DH and DH-PH-PH module show an autoinhibited conformation in which the substrate-binding site is occluded by the terminal DH helix and the two PH domains, and disrupting these elements relieves suppression in cells [#4]. This autoinhibited pool is recruited to signaling platforms and released by defined upstream cues. In semaphorin signaling, FARP2 basally associates with plexin-A1; Sema3A binding to neuropilin-1 triggers FARP2 dissociation, activating its Rac GEF activity, promoting Rnd1 recruitment and R-Ras downregulation, while its FERM domain sequesters PIPKIgamma661 from talin to drive axonal repulsion [#0]. Through a distinct interaction with the KRK motif of PlxnA4, FARP2 mediates Sema3A-induced Rac1 activation selectively for dendritic morphogenesis [#6]. At nectin-based adherens junctions, c-Src recruits and tyrosine-phosphorylates FARP2 to locally activate Cdc42 [#1], and aPKCι binds and phosphorylates FARP2 to form a positive-feedback loop driving epithelial polarity and tight junction formation [#5]. Beyond neurons and epithelia, FARP2 supports localized Rac1 activation in osteoclast podosomes during bone resorption [#3] and is required for TGF-β1-driven myofibroblast differentiation [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established FARP2 as a Cdc42-specific GEF that is recruited and activated at cell-cell adhesion sites, linking nectin/Src signaling to junction assembly.\",\n      \"evidence\": \"Co-IP, RNAi, GEF and tyrosine-phosphorylation assays at nectin-based junctions\",\n      \"pmids\": [\"15277544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how Src-mediated phosphorylation structurally relieves autoinhibition\", \"Selectivity between Cdc42 and Rac in this context not fully defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined FARP2 as the Rac GEF released from plexin-A1 upon Sema3A/neuropilin-1 engagement, coupling a guidance receptor to bifunctional Rac activation and talin/PIPKIgamma sequestration in axon repulsion.\",\n      \"evidence\": \"Reciprocal Co-IP, biochemical dissociation and GEF assays, axon repulsion functional readouts\",\n      \"pmids\": [\"16286926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism triggering dissociation from plexin-A1 at atomic resolution unknown\", \"Relative contribution of GEF activity versus PIPKIgamma sequestration not quantified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed FARP2 downstream of CD47/Src as a contributor to Cdc42/Rac activation supporting neuronal process development.\",\n      \"evidence\": \"FRG inhibition, CD47 overexpression, autophosphorylation assays and neuronal morphology in hippocampal neurons\",\n      \"pmids\": [\"17135401\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relied on inhibition rather than clean loss-of-function\", \"Functional redundancy with Vav2 not dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended FARP2's role beyond neurons by showing it drives localized Rac1 activation in osteoclast podosomes required for resorption and osteoclastogenesis.\",\n      \"evidence\": \"Live imaging, GTP-Rac1 pull-down, knockdown/knockout osteoclasts, resorption pit assay\",\n      \"pmids\": [\"20702777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream receptor recruiting FARP2 to podosomes not identified\", \"Link to integrin β3 activation mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural basis for FARP2 regulation, showing intramolecular autoinhibition of the GEF active site by the DH and tandem PH domains.\",\n      \"evidence\": \"X-ray crystallography of DH and DH-PH-PH modules with cell-based GEF activity validation\",\n      \"pmids\": [\"23375260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the activated, signal-released state not determined\", \"How phosphorylation or receptor binding triggers the conformational switch unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified FARP2 as an aPKCι binding partner and phosphorylation substrate forming a positive-feedback loop that activates Cdc42 to drive epithelial polarity and tight junction formation.\",\n      \"evidence\": \"Co-IP, phosphorylation assay, siRNA, GTP-Cdc42 pull-down, polarity and junction assays\",\n      \"pmids\": [\"30872454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation-induced detachment couples to Cdc42 loading not structurally defined\", \"In vivo relevance of the feedback loop not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved pathway specificity by showing FARP2 binds the PlxnA4 KRK motif to mediate Sema3A-induced Rac1 activation for dendrite morphogenesis while being dispensable for axon growth cone collapse.\",\n      \"evidence\": \"CRISPR/Cas9 KRK knock-in mice, FARP2 loss-of-function, Rac1 activity assays, dendritic and axon guidance readouts in vivo and in vitro\",\n      \"pmids\": [\"32499377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What distinguishes the plexin-A1 versus PlxnA4 FARP2 pools mechanistically unclear\", \"Effector specificity for dendrite versus axon outcomes not fully explained\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated FARP2 in pathological tissue remodeling, showing it is induced by TGF-β1 and required for myofibroblast differentiation and migration in corneal stromal fibroblasts.\",\n      \"evidence\": \"siRNA knockdown, qPCR, Western blot, α-SMA immunocytochemistry, scratch migration assay\",\n      \"pmids\": [\"41786192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo confirmation of a role in corneal fibrosis\", \"GTPase effector mediating the fibrotic phenotype not directly demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the structurally defined autoinhibited state is converted to the active state by the diverse upstream inputs (plexin release, Src and aPKCι phosphorylation) remains unresolved at the mechanistic level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of an activated/receptor-bound FARP2 state\", \"Quantitative rules for Rac1 versus Cdc42 selectivity across contexts undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005085\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PLXNA1\", \"NRP1\", \"PLXNA4\", \"PRKCI\", \"SRC\", \"PIP5K1C\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}