{"gene":"FARP1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1997,"finding":"FARP1 (CDEP) was cloned and found to encode a single polypeptide containing an ezrin-like FERM domain (band 4.1 superfamily) and Dbl homology (DH) and pleckstrin homology (PH) domains, establishing its domain architecture as a putative Rho guanine nucleotide exchange factor involved in cytoskeletal organization.","method":"cDNA cloning, sequence analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — molecular cloning with domain characterization replicated by subsequent studies confirming GEF activity","pmids":["9425278"],"is_preprint":false},{"year":2001,"finding":"FARP1 (CDEP) DH+PH domain peptide stimulates GDP dissociation from RhoA in vitro (guanine nucleotide exchange activity), and truncated CDEP induces focus formation (transformation) in NIH3T3 cells, establishing it as a functional Rho-family GEF with oncogenic potential.","method":"In vitro [3H]GDP dissociation assay using recombinant DH/PH domain peptide from Sf9 cells; NIH3T3 focus-formation assay","journal":"Osteoarthritis and cartilage","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro GEF activity assay plus cell-based transformation assay, two orthogonal methods in one study","pmids":["11680691"],"is_preprint":false},{"year":2009,"finding":"FARP1 acts downstream of transmembrane Semaphorin6A and PlexinA4 signaling to promote dendritic growth of lateral motor column neurons, and its Rho-GEF domain is necessary for this function; retinoid signaling induces FARP1 expression in these neurons.","method":"In vivo loss-of-function and gain-of-function in chick spinal cord; dominant-negative and domain-deletion constructs; morphometric analysis of dendritic arbors","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (Sema6A/PlexA4 pathway), domain-deletion mutagenesis, in vivo rescue experiments establishing pathway position","pmids":["19217374"],"is_preprint":false},{"year":2012,"finding":"FARP1 is postsynaptic and its FERM domain directly binds SynCAM 1, assembling a synaptic complex; FARP1 activates Rac1 in dendritic spines downstream of SynCAM 1 clustering, promotes F-actin assembly, increases synapse number and modulates spine morphology, and triggers a retrograde signal regulating active zone composition via SynCAM 1.","method":"Proteomic analysis of SynCAM 1 KO synaptic membranes; co-immunoprecipitation; live imaging of dendritic filopodial dynamics; Rac1 activity assays; overexpression and knockdown in neurons; F-actin staining","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, Rac1 activity assay, KO mouse model, multiple orthogonal functional readouts, SynCAM 1 epistasis established","pmids":["23209303"],"is_preprint":false},{"year":2014,"finding":"Farp1 interacts with the Neuropilin-1/PlexinA1 receptor complex and is required for Sema3A-induced dendritic arborization; Sema3A regulates dendritic F-actin distribution via Farp1, placing Farp1 downstream of the Neuropilin-1/PlexinA1 complex as a Rac1 activator.","method":"Co-immunoprecipitation; knockdown in hippocampal neurons; F-actin imaging; dendritic morphometry; pharmacological silencing (TTX) and proteasome inhibition","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, loss-of-function with specific dendritic phenotype, F-actin readout, epistasis with Sema3A/PlexinA1 pathway, single lab but multiple orthogonal methods","pmids":["24899721"],"is_preprint":false},{"year":2015,"finding":"MAP4K4 directly phosphorylates FARP1 (at a pTL motif) and co-immunoprecipitates with FARP1; MAP4K4 inhibition increases neurite outgrowth in SH-SY5Y cells, a process known to involve FARP1, suggesting MAP4K4 exerts cytoskeletal effects partly through FARP1 phosphorylation.","method":"Phosphoproteomic profiling of MAP4K4 inhibition; in vitro kinase assay; co-immunoprecipitation; neurite outgrowth assay","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus Co-IP establishes direct phosphorylation, but functional link to neurite outgrowth is inferred rather than directly demonstrated via FARP1 mutation","pmids":["26422651"],"is_preprint":false},{"year":2016,"finding":"siRNA-mediated knockdown of FARP1 in PC12 cells leads to significant inhibition of Cdc42 activity, identifying FARP1 as an upstream activator of Cdc42 in neuroendocrine cells.","method":"siRNA knockdown; ELISA-based Cdc42 activity assay","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with specific GTPase activity readout, single lab, single method for the FARP1-Cdc42 link","pmids":["26911374"],"is_preprint":false},{"year":2018,"finding":"Crystal structures of the FARP1 FERM domain (zebrafish) reveal a three-lobed clover fold with a positively charged surface patch that mediates specific binding to phospholipids in vitro and underlies plasma membrane localization and recruitment to postsynaptic sites in neurons.","method":"X-ray crystallography; in vitro lipid-binding assay; cell-based membrane localization assay with surface-patch mutants; neuronal imaging","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with in vitro lipid binding and mutagenesis, validated in cell-based localization assay","pmids":["29992992"],"is_preprint":false},{"year":2019,"finding":"Knockdown of FARP1 in A-375 melanoma cells reduces phospho-MEK and phospho-ERK levels, linking FARP1 to MAPK pathway activation and cell proliferation/motility.","method":"siRNA knockdown; Western blot for pMEK/MEK and pERK/ERK; CCK8 proliferation assay; wound-healing and Transwell invasion assays","journal":"The American Journal of dermatopathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach, no direct mechanistic connection between FARP1 GEF activity and MAPK pathway established","pmids":["31021836"],"is_preprint":false},{"year":2021,"finding":"FARP1 is an essential Rac-GEF effector downstream of EGFR and c-Met receptor tyrosine kinases for Rac1-mediated lung cancer cell migration; FARP1 controls distinctive aspects of ruffle dynamics and operates non-redundantly with ARHGEF39 and TIAM2; the AXL-Gab1-PI3K axis is a leading upstream regulator conferring pro-motility traits downstream of EGFR.","method":"RNAi screen; siRNA knockdown; Rac1 activity assay; live-cell imaging of ruffle dynamics; migration assays; epistasis with PI3K inhibition","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic RNAi screen, Rac1 activity assay, live imaging, PI3K epistasis, single lab","pmids":["34731623"],"is_preprint":false},{"year":2022,"finding":"In Drosophila border cells, Cdep (FARP1 ortholog) functions as a Rac GEF downstream of the Scribble/Dlg/Lgl basolateral polarity complex to promote follower-cell motility and cluster cohesion during collective migration; relocalization of Cdep::GFP partially rescues Scribble knockdown, placing Cdep as a major downstream effector of basolateral proteins.","method":"Genetic knockdown/rescue in Drosophila border cells; live imaging; GFP-fusion relocalization rescue experiment; epistasis analysis with Scribble, Dlg, Lgl","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo epistasis, rescue experiment, multiple genetic combinations, live imaging in established model system","pmids":["36347240"],"is_preprint":false},{"year":2023,"finding":"FARP1 acts as a PI3K-regulated GEF downstream of Gi/o-coupled GPCRs (OXER1 and LPA receptor) via a Gβγ/PKCα/FARP1/Cdc42 axis to drive formation of actin-rich tunneling nanotube (TNT)-like structures in adrenocortical cancer cells.","method":"siRNA knockdown; pertussis toxin and biased antagonist pharmacology; PI3K and PLCβ inhibition; Cdc42 activity assay; live-cell imaging of TNT structures","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via pharmacological and siRNA-based pathway dissection, Cdc42 activity assay, specific TNT phenotype, single lab","pmids":["37390986"],"is_preprint":false},{"year":2026,"finding":"GPR81 (lactate receptor) recruits FARP1 to activate RAC1, promoting GLUT4 translocation independently of insulin signaling in skeletal muscle; GPR81-FARP1-Rac1 axis mediates insulin-independent glucose uptake.","method":"Genetic knockout of GPR81 in skeletal muscle; ectopic expression; pharmacological GPR81 activation; GLUT4 translocation assay; glucose tolerance test; mechanistic pathway analysis","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and ectopic expression with defined metabolic phenotype, GLUT4 translocation readout, pathway placement, single lab","pmids":["41530347"],"is_preprint":false},{"year":2026,"finding":"FARP1 is a pivotal Rac-GEF effector of cMET receptor tyrosine kinase in androgen-independent prostate cancer cells; HGF/cMET stimulation promotes formation of actin-rich protrusions through a PI3K-FARP1-Rac1-dependent pathway, and FARP1 relocalizes to actin-rich protrusions in response to HGF, acting independently of VAV2.","method":"Unbiased RNAi screen targeting Rac-GEFs; siRNA knockdown; Rac1 activity assay; live-cell imaging of actin protrusions; PI3K inhibition epistasis; migration and invasion assays","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi screen, Rac1 activity assay, FARP1 relocalization imaging, PI3K epistasis, single lab","pmids":["42175718"],"is_preprint":false}],"current_model":"FARP1 is a multi-domain protein (FERM, DH/RhoGEF, PH domains) whose FERM domain binds phospholipids (via a conserved positively charged surface patch, defined by crystal structure) and cell-surface receptors (SynCAM 1, PlexinA4, Neuropilin-1/PlexinA1) to localize it to the plasma membrane and postsynaptic sites, where its DH domain activates Rac1 and Cdc42 downstream of diverse upstream signals including semaphorin/plexin receptors, SynCAM 1, receptor tyrosine kinases (EGFR, c-Met), Gi/o-coupled GPCRs (via Gβγ/PKCα), and the lactate receptor GPR81, driving actin cytoskeleton reorganization, dendritic growth and spine morphology, synaptic development with retrograde transsynaptic signaling, cancer cell migration/invasion, and GLUT4 translocation; additionally, MAP4K4 phosphorylates FARP1 directly, and in Drosophila the ortholog Cdep is placed downstream of the Scribble/Dlg/Lgl basolateral polarity complex to activate Rac and drive collective cell migration."},"narrative":{"mechanistic_narrative":"FARP1 is a multidomain Rho-family guanine nucleotide exchange factor that couples cell-surface receptors to actin cytoskeleton remodeling, driving neuronal dendritic and synaptic development as well as cancer cell motility [PMID:9425278, PMID:19217374, PMID:23209303]. Its domain architecture comprises an N-terminal FERM domain (band 4.1 superfamily) together with tandem Dbl-homology (DH) and pleckstrin-homology (PH) domains [PMID:9425278], and its DH/PH module is a functional GEF that stimulates GDP dissociation from RhoA in vitro and is sufficient to transform NIH3T3 cells [PMID:11680691]. The FERM domain adopts a three-lobed clover fold bearing a positively charged surface patch that binds phospholipids and directs plasma-membrane and postsynaptic localization [PMID:29992992], and it also engages cell-surface receptors directly: FARP1 binds SynCAM 1 to assemble a postsynaptic complex that activates Rac1, builds F-actin in dendritic spines, and triggers retrograde transsynaptic signaling controlling active-zone composition [PMID:23209303]. In neurons, FARP1 operates downstream of semaphorin/plexin signaling—the transmembrane Sema6A/PlexinA4 pathway and the Sema3A–Neuropilin-1/PlexinA1 complex—to promote dendritic arborization through its Rho-GEF activity [PMID:19217374, PMID:24899721]. In cancer and metabolic contexts, FARP1 functions as a Rac1/Cdc42 activator downstream of diverse upstream inputs: EGFR and c-Met receptor tyrosine kinases through an AXL/PI3K axis for lung and prostate cancer cell migration and protrusion formation [PMID:34731623, PMID:42175718], Gi/o-coupled GPCRs via a Gβγ/PKCα/Cdc42 axis driving tunneling-nanotube formation [PMID:37390986], and the lactate receptor GPR81 to drive insulin-independent GLUT4 translocation in skeletal muscle [PMID:41530347]. FARP1 is directly phosphorylated by MAP4K4 at a pTL motif [PMID:26422651]. The Drosophila ortholog Cdep acts as a Rac-GEF downstream of the Scribble/Dlg/Lgl basolateral polarity complex during collective border-cell migration, indicating a conserved role linking cell polarity to Rac activation [PMID:36347240].","teleology":[{"year":1997,"claim":"Established the molecular identity and domain architecture of FARP1, defining it as a candidate Rho-GEF linking membrane/cytoskeletal scaffolding (FERM) to small-GTPase regulation (DH/PH).","evidence":"cDNA cloning and sequence analysis revealing FERM, DH, and PH domains","pmids":["9425278"],"confidence":"Medium","gaps":["No biochemical demonstration of GEF activity","GTPase specificity undefined","No cellular or in vivo function tested"]},{"year":2001,"claim":"Demonstrated FARP1 is a functional Rho-family GEF with oncogenic potential, converting the predicted domain architecture into measured enzymatic activity.","evidence":"In vitro [3H]GDP dissociation assay with recombinant DH/PH peptide and NIH3T3 focus-formation assay","pmids":["11680691"],"confidence":"High","gaps":["RhoA tested in vitro but physiological substrate in cells unresolved","Upstream activating signals unknown","Role of FERM domain not addressed"]},{"year":2009,"claim":"Placed FARP1 within an intact receptor signaling pathway in vivo, showing its GEF domain is required for semaphorin/plexin-driven dendritic growth.","evidence":"In vivo loss/gain-of-function and domain-deletion in chick spinal cord motor neurons","pmids":["19217374"],"confidence":"High","gaps":["Direct biochemical link between PlexinA4 and FARP1 not shown","Which GTPase is activated in this context unspecified","Mechanism of retinoid-induced expression not detailed"]},{"year":2012,"claim":"Identified a direct receptor partner and a complete signaling module, showing FERM-domain binding to SynCAM 1 localizes FARP1 to activate Rac1 in spines and drive transsynaptic signaling.","evidence":"SynCAM 1 KO proteomics, reciprocal Co-IP, Rac1 activity assays, F-actin imaging in neurons","pmids":["23209303"],"confidence":"High","gaps":["Structural basis of FERM-SynCAM 1 binding not resolved","Mechanism of retrograde signal transmission incomplete","Relationship to plexin pathway inputs unclear"]},{"year":2014,"claim":"Extended FARP1's receptor repertoire to the Neuropilin-1/PlexinA1 complex, establishing it as a Rac1 activator for Sema3A-induced dendritic arborization.","evidence":"Co-IP, knockdown and F-actin/dendritic morphometry in hippocampal neurons","pmids":["24899721"],"confidence":"High","gaps":["Whether FARP1 binds the receptor complex directly versus indirectly unresolved","Domain mediating the interaction not mapped"]},{"year":2015,"claim":"Identified FARP1 as a direct phosphorylation substrate of MAP4K4, introducing post-translational regulation of FARP1.","evidence":"Phosphoproteomics, in vitro kinase assay, Co-IP, neurite outgrowth assay in SH-SY5Y cells","pmids":["26422651"],"confidence":"Medium","gaps":["Functional consequence of phosphorylation inferred, not tested via phospho-mutant FARP1","Effect on GEF activity unknown","pTL site role in localization undefined"]},{"year":2016,"claim":"Broadened FARP1's GTPase output, showing it activates Cdc42 in neuroendocrine cells rather than only Rho/Rac.","evidence":"siRNA knockdown and ELISA-based Cdc42 activity assay in PC12 cells","pmids":["26911374"],"confidence":"Medium","gaps":["Single method for the FARP1-Cdc42 link","Upstream receptor not identified","Direct GEF activity toward Cdc42 not measured biochemically"]},{"year":2018,"claim":"Provided the structural basis for membrane targeting, showing the FERM domain's positively charged surface patch binds phospholipids and controls localization.","evidence":"X-ray crystallography of zebrafish FERM domain, lipid-binding assays, surface-patch mutants in cells/neurons","pmids":["29992992"],"confidence":"High","gaps":["Specific phospholipid species not fully defined","How lipid binding integrates with receptor binding unresolved","Full-length protein structure unknown"]},{"year":2021,"claim":"Defined FARP1 as a non-redundant Rac-GEF effector of RTK signaling in cancer cell migration, connecting it to the EGFR/c-Met–AXL–PI3K axis.","evidence":"RNAi screen, Rac1 activity assay, live imaging of ruffle dynamics, PI3K epistasis in lung cancer cells","pmids":["34731623"],"confidence":"Medium","gaps":["Direct physical link between RTKs and FARP1 not established","Mechanism of PI3K-dependent activation unclear","Single cell-type/lab"]},{"year":2022,"claim":"Demonstrated evolutionary conservation of FARP1 function, placing the ortholog Cdep downstream of the Scribble/Dlg/Lgl polarity complex to drive collective migration.","evidence":"Genetic knockdown/rescue, GFP-relocalization rescue and epistasis in Drosophila border cells","pmids":["36347240"],"confidence":"High","gaps":["Biochemical link between basolateral complex and Cdep unmapped","Conservation of this pathway in mammalian FARP1 untested"]},{"year":2023,"claim":"Established FARP1 as a GPCR-coupled GEF, linking Gi/o receptors through a Gβγ/PKCα/Cdc42 axis to tunneling-nanotube formation.","evidence":"siRNA, pertussis toxin and biased-antagonist pharmacology, PI3K/PLCβ inhibition, Cdc42 activity assay in adrenocortical cancer cells","pmids":["37390986"],"confidence":"Medium","gaps":["Direct activation of FARP1 by Gβγ or PKCα not biochemically shown","Single cell model"]},{"year":2026,"claim":"Connected FARP1 to metabolic regulation, showing the GPR81–FARP1–Rac1 axis drives insulin-independent GLUT4 translocation in muscle.","evidence":"Skeletal-muscle GPR81 knockout, ectopic expression, GLUT4 translocation and glucose tolerance assays","pmids":["41530347"],"confidence":"Medium","gaps":["Direct GPR81-FARP1 interaction not biochemically defined","How FARP1 selects Rac1 here versus Cdc42 elsewhere unresolved"]},{"year":2026,"claim":"Confirmed FARP1 as a c-Met Rac-GEF effector in a second cancer setting, showing HGF-induced PI3K-dependent recruitment to actin protrusions independent of VAV2.","evidence":"RNAi screen, Rac1 activity assay, FARP1 relocalization imaging, PI3K epistasis in prostate cancer cells","pmids":["42175718"],"confidence":"Medium","gaps":["Direct c-Met–FARP1 binding not shown","Mechanism of PI3K-dependent recruitment unresolved"]},{"year":null,"claim":"How FARP1 integrates simultaneous lipid binding, receptor binding, and phosphorylation to select among RhoA, Rac1, and Cdc42 in a context-dependent manner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No full-length structure showing FERM-DH/PH autoregulation","GTPase selectivity determinants undefined","Direct receptor-binding interfaces beyond SynCAM 1 unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3,6]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,4]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,13]}],"pathway":[],"complexes":[],"partners":["SYNCAM 1","PLEXINA4","NEUROPILIN-1","PLEXINA1","MAP4K4","GPR81"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y4F1","full_name":"FERM, ARHGEF and pleckstrin domain-containing protein 1","aliases":["Chondrocyte-derived ezrin-like protein","FERM, RhoGEF and pleckstrin domain-containing protein 1","Pleckstrin homology domain-containing family C member 2","PH domain-containing family C member 2"],"length_aa":1045,"mass_kda":118.6,"function":"Functions as a guanine nucleotide exchange factor for RAC1. May play a role in semaphorin signaling. Plays a role in the assembly and disassembly of dendritic filopodia, the formation of dendritic spines, regulation of dendrite length and ultimately the formation of synapses (By similarity)","subcellular_location":"Cell membrane; Synapse; Synapse, synaptosome; Cytoplasm, cytosol; Cell projection, filopodium; Cell projection, dendrite; Cell projection, dendritic spine","url":"https://www.uniprot.org/uniprotkb/Q9Y4F1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FARP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000152767","cell_line_id":"CID000576","localizations":[{"compartment":"membrane","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"SDC3","stoichiometry":10.0},{"gene":"C17ORF80","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000576","total_profiled":1310},"omim":[{"mim_id":"618867","title":"RAS HOMOLOG GENE FAMILY, MEMBER F, FILOPODIA-ASSOCIATED; RHOF","url":"https://www.omim.org/entry/618867"},{"mim_id":"617586","title":"FERM, ARHGEF, AND PLECKSTRIN DOMAINS-CONTAINING PROTEIN 2; FARP2","url":"https://www.omim.org/entry/617586"},{"mim_id":"604280","title":"PLEXIN A4; PLXNA4","url":"https://www.omim.org/entry/604280"},{"mim_id":"602654","title":"FERM, ARHGEF, AND PLECKSTRIN DOMAINS-CONTAINING PROTEIN 1; FARP1","url":"https://www.omim.org/entry/602654"},{"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/FARP1"},"hgnc":{"alias_symbol":["CDEP","PLEKHC2","MGC87400","PPP1R75","GLCC1"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y4F1","domains":[{"cath_id":"3.10.20.90","chopping":"38-116","consensus_level":"medium","plddt":91.9475,"start":38,"end":116},{"cath_id":"2.30.29.30","chopping":"226-323_337-357","consensus_level":"medium","plddt":88.841,"start":226,"end":357},{"cath_id":"1.20.900.10","chopping":"539-746","consensus_level":"high","plddt":93.3521,"start":539,"end":746},{"cath_id":"2.30.29.30","chopping":"749-861","consensus_level":"high","plddt":92.7157,"start":749,"end":861},{"cath_id":"2.30.29.30","chopping":"934-1025","consensus_level":"high","plddt":92.9967,"start":934,"end":1025}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4F1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4F1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4F1-F1-predicted_aligned_error_v6.png","plddt_mean":76.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FARP1","jax_strain_url":"https://www.jax.org/strain/search?query=FARP1"},"sequence":{"accession":"Q9Y4F1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y4F1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y4F1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4F1"}},"corpus_meta":[{"pmid":"31375671","id":"PMC_31375671","title":"LncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31375671","citation_count":284,"is_preprint":false},{"pmid":"20126683","id":"PMC_20126683","title":"Selective isolation of live/dead cells using contactless dielectrophoresis (cDEP).","date":"2010","source":"Lab on a chip","url":"https://pubmed.ncbi.nlm.nih.gov/20126683","citation_count":179,"is_preprint":false},{"pmid":"23209303","id":"PMC_23209303","title":"The novel synaptogenic protein Farp1 links postsynaptic cytoskeletal dynamics and transsynaptic organization.","date":"2012","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23209303","citation_count":91,"is_preprint":false},{"pmid":"19217374","id":"PMC_19217374","title":"FARP1 promotes the dendritic growth of spinal motor neuron subtypes through transmembrane Semaphorin6A and PlexinA4 signaling.","date":"2009","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/19217374","citation_count":78,"is_preprint":false},{"pmid":"24899721","id":"PMC_24899721","title":"Activity-dependent regulation of dendritic complexity by semaphorin 3A through Farp1.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24899721","citation_count":46,"is_preprint":false},{"pmid":"9425278","id":"PMC_9425278","title":"Molecular cloning and characterization of CDEP, a novel human protein containing the ezrin-like domain of the band 4.1 superfamily and the Dbl homology domain of Rho guanine nucleotide exchange factors.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9425278","citation_count":31,"is_preprint":false},{"pmid":"34731623","id":"PMC_34731623","title":"FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34731623","citation_count":30,"is_preprint":false},{"pmid":"26911374","id":"PMC_26911374","title":"Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression.","date":"2016","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26911374","citation_count":24,"is_preprint":false},{"pmid":"36347240","id":"PMC_36347240","title":"A Scribble/Cdep/Rac pathway controls follower-cell crawling and cluster cohesion during collective border-cell migration.","date":"2022","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/36347240","citation_count":19,"is_preprint":false},{"pmid":"29992992","id":"PMC_29992992","title":"Structural analyses of FERM domain-mediated membrane localization of FARP1.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29992992","citation_count":15,"is_preprint":false},{"pmid":"26422651","id":"PMC_26422651","title":"MAP4K4 Is a Threonine Kinase That Phosphorylates FARP1.","date":"2015","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/26422651","citation_count":14,"is_preprint":false},{"pmid":"37390986","id":"PMC_37390986","title":"Gi/o GPCRs drive the formation of actin-rich tunneling nanotubes in cancer cells via a Gβγ/PKCα/FARP1/Cdc42 axis.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37390986","citation_count":14,"is_preprint":false},{"pmid":"11680691","id":"PMC_11680691","title":"Chondrocyte-derived ezrin-like domain containing protein (CDEP), a rho guanine nucleotide exchange factor, is inducible in chondrocytes by parathyroid hormone and cyclic AMP and has transforming activity in NIH3T3 cells.","date":"2001","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/11680691","citation_count":14,"is_preprint":false},{"pmid":"32588496","id":"PMC_32588496","title":"FARP-1 deletion is associated with lack of response to autism treatment by early start denver model in a multiplex family.","date":"2020","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32588496","citation_count":11,"is_preprint":false},{"pmid":"34196212","id":"PMC_34196212","title":"An oncogenic lncRNA, GLCC1, promotes tumorigenesis in gastric carcinoma by enhancing the c-Myc/IGF2BP1 interaction.","date":"2021","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/34196212","citation_count":7,"is_preprint":false},{"pmid":"22078224","id":"PMC_22078224","title":"Consistent Differential Expression Pattern (CDEP) on microarray to identify genes related to metastatic behavior.","date":"2011","source":"BMC bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/22078224","citation_count":7,"is_preprint":false},{"pmid":"28208767","id":"PMC_28208767","title":"Alternative cDEP Design to Facilitate Cell Isolation for Identification by Raman Spectroscopy.","date":"2017","source":"Sensors (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/28208767","citation_count":7,"is_preprint":false},{"pmid":"12182086","id":"PMC_12182086","title":"[Cloning and characterization of cuticle degrading enzyme CDEP-1 from Beauveria bassiana].","date":"2002","source":"Yi chuan xue bao = Acta genetica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/12182086","citation_count":5,"is_preprint":false},{"pmid":"31021836","id":"PMC_31021836","title":"FARP1 Facilitates Cell Proliferation Through Modulating MAPK Signaling Pathway in Cutaneous Melanoma.","date":"2019","source":"The American Journal of dermatopathology","url":"https://pubmed.ncbi.nlm.nih.gov/31021836","citation_count":4,"is_preprint":false},{"pmid":"41530347","id":"PMC_41530347","title":"Lactate-activated GPR81/FARP1 signaling drives insulin-independent glucose uptake and metabolic control.","date":"2026","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/41530347","citation_count":1,"is_preprint":false},{"pmid":"39583578","id":"PMC_39583578","title":"Conserved region of human TDP-43 is structurally similar to membrane binding protein FARP1 and protein chaperons BAG6 and CYP33.","date":"2024","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/39583578","citation_count":1,"is_preprint":false},{"pmid":"42175718","id":"PMC_42175718","title":"FARP1 mediates cMET-driven motility in androgen-independent prostate cancer cells.","date":"2026","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/42175718","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11849,"output_tokens":3740,"usd":0.045824,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11323,"output_tokens":4296,"usd":0.082007,"stage2_stop_reason":"end_turn"},"total_usd":0.127831,"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\": 1997,\n      \"finding\": \"FARP1 (CDEP) was cloned and found to encode a single polypeptide containing an ezrin-like FERM domain (band 4.1 superfamily) and Dbl homology (DH) and pleckstrin homology (PH) domains, establishing its domain architecture as a putative Rho guanine nucleotide exchange factor involved in cytoskeletal organization.\",\n      \"method\": \"cDNA cloning, sequence analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — molecular cloning with domain characterization replicated by subsequent studies confirming GEF activity\",\n      \"pmids\": [\"9425278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"FARP1 (CDEP) DH+PH domain peptide stimulates GDP dissociation from RhoA in vitro (guanine nucleotide exchange activity), and truncated CDEP induces focus formation (transformation) in NIH3T3 cells, establishing it as a functional Rho-family GEF with oncogenic potential.\",\n      \"method\": \"In vitro [3H]GDP dissociation assay using recombinant DH/PH domain peptide from Sf9 cells; NIH3T3 focus-formation assay\",\n      \"journal\": \"Osteoarthritis and cartilage\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro GEF activity assay plus cell-based transformation assay, two orthogonal methods in one study\",\n      \"pmids\": [\"11680691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FARP1 acts downstream of transmembrane Semaphorin6A and PlexinA4 signaling to promote dendritic growth of lateral motor column neurons, and its Rho-GEF domain is necessary for this function; retinoid signaling induces FARP1 expression in these neurons.\",\n      \"method\": \"In vivo loss-of-function and gain-of-function in chick spinal cord; dominant-negative and domain-deletion constructs; morphometric analysis of dendritic arbors\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (Sema6A/PlexA4 pathway), domain-deletion mutagenesis, in vivo rescue experiments establishing pathway position\",\n      \"pmids\": [\"19217374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FARP1 is postsynaptic and its FERM domain directly binds SynCAM 1, assembling a synaptic complex; FARP1 activates Rac1 in dendritic spines downstream of SynCAM 1 clustering, promotes F-actin assembly, increases synapse number and modulates spine morphology, and triggers a retrograde signal regulating active zone composition via SynCAM 1.\",\n      \"method\": \"Proteomic analysis of SynCAM 1 KO synaptic membranes; co-immunoprecipitation; live imaging of dendritic filopodial dynamics; Rac1 activity assays; overexpression and knockdown in neurons; F-actin staining\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, Rac1 activity assay, KO mouse model, multiple orthogonal functional readouts, SynCAM 1 epistasis established\",\n      \"pmids\": [\"23209303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Farp1 interacts with the Neuropilin-1/PlexinA1 receptor complex and is required for Sema3A-induced dendritic arborization; Sema3A regulates dendritic F-actin distribution via Farp1, placing Farp1 downstream of the Neuropilin-1/PlexinA1 complex as a Rac1 activator.\",\n      \"method\": \"Co-immunoprecipitation; knockdown in hippocampal neurons; F-actin imaging; dendritic morphometry; pharmacological silencing (TTX) and proteasome inhibition\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, loss-of-function with specific dendritic phenotype, F-actin readout, epistasis with Sema3A/PlexinA1 pathway, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24899721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAP4K4 directly phosphorylates FARP1 (at a pTL motif) and co-immunoprecipitates with FARP1; MAP4K4 inhibition increases neurite outgrowth in SH-SY5Y cells, a process known to involve FARP1, suggesting MAP4K4 exerts cytoskeletal effects partly through FARP1 phosphorylation.\",\n      \"method\": \"Phosphoproteomic profiling of MAP4K4 inhibition; in vitro kinase assay; co-immunoprecipitation; neurite outgrowth assay\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus Co-IP establishes direct phosphorylation, but functional link to neurite outgrowth is inferred rather than directly demonstrated via FARP1 mutation\",\n      \"pmids\": [\"26422651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"siRNA-mediated knockdown of FARP1 in PC12 cells leads to significant inhibition of Cdc42 activity, identifying FARP1 as an upstream activator of Cdc42 in neuroendocrine cells.\",\n      \"method\": \"siRNA knockdown; ELISA-based Cdc42 activity assay\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with specific GTPase activity readout, single lab, single method for the FARP1-Cdc42 link\",\n      \"pmids\": [\"26911374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structures of the FARP1 FERM domain (zebrafish) reveal a three-lobed clover fold with a positively charged surface patch that mediates specific binding to phospholipids in vitro and underlies plasma membrane localization and recruitment to postsynaptic sites in neurons.\",\n      \"method\": \"X-ray crystallography; in vitro lipid-binding assay; cell-based membrane localization assay with surface-patch mutants; neuronal imaging\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with in vitro lipid binding and mutagenesis, validated in cell-based localization assay\",\n      \"pmids\": [\"29992992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knockdown of FARP1 in A-375 melanoma cells reduces phospho-MEK and phospho-ERK levels, linking FARP1 to MAPK pathway activation and cell proliferation/motility.\",\n      \"method\": \"siRNA knockdown; Western blot for pMEK/MEK and pERK/ERK; CCK8 proliferation assay; wound-healing and Transwell invasion assays\",\n      \"journal\": \"The American Journal of dermatopathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach, no direct mechanistic connection between FARP1 GEF activity and MAPK pathway established\",\n      \"pmids\": [\"31021836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FARP1 is an essential Rac-GEF effector downstream of EGFR and c-Met receptor tyrosine kinases for Rac1-mediated lung cancer cell migration; FARP1 controls distinctive aspects of ruffle dynamics and operates non-redundantly with ARHGEF39 and TIAM2; the AXL-Gab1-PI3K axis is a leading upstream regulator conferring pro-motility traits downstream of EGFR.\",\n      \"method\": \"RNAi screen; siRNA knockdown; Rac1 activity assay; live-cell imaging of ruffle dynamics; migration assays; epistasis with PI3K inhibition\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic RNAi screen, Rac1 activity assay, live imaging, PI3K epistasis, single lab\",\n      \"pmids\": [\"34731623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Drosophila border cells, Cdep (FARP1 ortholog) functions as a Rac GEF downstream of the Scribble/Dlg/Lgl basolateral polarity complex to promote follower-cell motility and cluster cohesion during collective migration; relocalization of Cdep::GFP partially rescues Scribble knockdown, placing Cdep as a major downstream effector of basolateral proteins.\",\n      \"method\": \"Genetic knockdown/rescue in Drosophila border cells; live imaging; GFP-fusion relocalization rescue experiment; epistasis analysis with Scribble, Dlg, Lgl\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo epistasis, rescue experiment, multiple genetic combinations, live imaging in established model system\",\n      \"pmids\": [\"36347240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FARP1 acts as a PI3K-regulated GEF downstream of Gi/o-coupled GPCRs (OXER1 and LPA receptor) via a Gβγ/PKCα/FARP1/Cdc42 axis to drive formation of actin-rich tunneling nanotube (TNT)-like structures in adrenocortical cancer cells.\",\n      \"method\": \"siRNA knockdown; pertussis toxin and biased antagonist pharmacology; PI3K and PLCβ inhibition; Cdc42 activity assay; live-cell imaging of TNT structures\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via pharmacological and siRNA-based pathway dissection, Cdc42 activity assay, specific TNT phenotype, single lab\",\n      \"pmids\": [\"37390986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GPR81 (lactate receptor) recruits FARP1 to activate RAC1, promoting GLUT4 translocation independently of insulin signaling in skeletal muscle; GPR81-FARP1-Rac1 axis mediates insulin-independent glucose uptake.\",\n      \"method\": \"Genetic knockout of GPR81 in skeletal muscle; ectopic expression; pharmacological GPR81 activation; GLUT4 translocation assay; glucose tolerance test; mechanistic pathway analysis\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and ectopic expression with defined metabolic phenotype, GLUT4 translocation readout, pathway placement, single lab\",\n      \"pmids\": [\"41530347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FARP1 is a pivotal Rac-GEF effector of cMET receptor tyrosine kinase in androgen-independent prostate cancer cells; HGF/cMET stimulation promotes formation of actin-rich protrusions through a PI3K-FARP1-Rac1-dependent pathway, and FARP1 relocalizes to actin-rich protrusions in response to HGF, acting independently of VAV2.\",\n      \"method\": \"Unbiased RNAi screen targeting Rac-GEFs; siRNA knockdown; Rac1 activity assay; live-cell imaging of actin protrusions; PI3K inhibition epistasis; migration and invasion assays\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi screen, Rac1 activity assay, FARP1 relocalization imaging, PI3K epistasis, single lab\",\n      \"pmids\": [\"42175718\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FARP1 is a multi-domain protein (FERM, DH/RhoGEF, PH domains) whose FERM domain binds phospholipids (via a conserved positively charged surface patch, defined by crystal structure) and cell-surface receptors (SynCAM 1, PlexinA4, Neuropilin-1/PlexinA1) to localize it to the plasma membrane and postsynaptic sites, where its DH domain activates Rac1 and Cdc42 downstream of diverse upstream signals including semaphorin/plexin receptors, SynCAM 1, receptor tyrosine kinases (EGFR, c-Met), Gi/o-coupled GPCRs (via Gβγ/PKCα), and the lactate receptor GPR81, driving actin cytoskeleton reorganization, dendritic growth and spine morphology, synaptic development with retrograde transsynaptic signaling, cancer cell migration/invasion, and GLUT4 translocation; additionally, MAP4K4 phosphorylates FARP1 directly, and in Drosophila the ortholog Cdep is placed downstream of the Scribble/Dlg/Lgl basolateral polarity complex to activate Rac and drive collective cell migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FARP1 is a multidomain Rho-family guanine nucleotide exchange factor that couples cell-surface receptors to actin cytoskeleton remodeling, driving neuronal dendritic and synaptic development as well as cancer cell motility [#0, #2, #3]. Its domain architecture comprises an N-terminal FERM domain (band 4.1 superfamily) together with tandem Dbl-homology (DH) and pleckstrin-homology (PH) domains [#0], and its DH/PH module is a functional GEF that stimulates GDP dissociation from RhoA in vitro and is sufficient to transform NIH3T3 cells [#1]. The FERM domain adopts a three-lobed clover fold bearing a positively charged surface patch that binds phospholipids and directs plasma-membrane and postsynaptic localization [#7], and it also engages cell-surface receptors directly: FARP1 binds SynCAM 1 to assemble a postsynaptic complex that activates Rac1, builds F-actin in dendritic spines, and triggers retrograde transsynaptic signaling controlling active-zone composition [#3]. In neurons, FARP1 operates downstream of semaphorin/plexin signaling—the transmembrane Sema6A/PlexinA4 pathway and the Sema3A–Neuropilin-1/PlexinA1 complex—to promote dendritic arborization through its Rho-GEF activity [#2, #4]. In cancer and metabolic contexts, FARP1 functions as a Rac1/Cdc42 activator downstream of diverse upstream inputs: EGFR and c-Met receptor tyrosine kinases through an AXL/PI3K axis for lung and prostate cancer cell migration and protrusion formation [#9, #13], Gi/o-coupled GPCRs via a Gβγ/PKCα/Cdc42 axis driving tunneling-nanotube formation [#11], and the lactate receptor GPR81 to drive insulin-independent GLUT4 translocation in skeletal muscle [#12]. FARP1 is directly phosphorylated by MAP4K4 at a pTL motif [#5]. The Drosophila ortholog Cdep acts as a Rac-GEF downstream of the Scribble/Dlg/Lgl basolateral polarity complex during collective border-cell migration, indicating a conserved role linking cell polarity to Rac activation [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the molecular identity and domain architecture of FARP1, defining it as a candidate Rho-GEF linking membrane/cytoskeletal scaffolding (FERM) to small-GTPase regulation (DH/PH).\",\n      \"evidence\": \"cDNA cloning and sequence analysis revealing FERM, DH, and PH domains\",\n      \"pmids\": [\"9425278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical demonstration of GEF activity\", \"GTPase specificity undefined\", \"No cellular or in vivo function tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated FARP1 is a functional Rho-family GEF with oncogenic potential, converting the predicted domain architecture into measured enzymatic activity.\",\n      \"evidence\": \"In vitro [3H]GDP dissociation assay with recombinant DH/PH peptide and NIH3T3 focus-formation assay\",\n      \"pmids\": [\"11680691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RhoA tested in vitro but physiological substrate in cells unresolved\", \"Upstream activating signals unknown\", \"Role of FERM domain not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed FARP1 within an intact receptor signaling pathway in vivo, showing its GEF domain is required for semaphorin/plexin-driven dendritic growth.\",\n      \"evidence\": \"In vivo loss/gain-of-function and domain-deletion in chick spinal cord motor neurons\",\n      \"pmids\": [\"19217374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between PlexinA4 and FARP1 not shown\", \"Which GTPase is activated in this context unspecified\", \"Mechanism of retinoid-induced expression not detailed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a direct receptor partner and a complete signaling module, showing FERM-domain binding to SynCAM 1 localizes FARP1 to activate Rac1 in spines and drive transsynaptic signaling.\",\n      \"evidence\": \"SynCAM 1 KO proteomics, reciprocal Co-IP, Rac1 activity assays, F-actin imaging in neurons\",\n      \"pmids\": [\"23209303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FERM-SynCAM 1 binding not resolved\", \"Mechanism of retrograde signal transmission incomplete\", \"Relationship to plexin pathway inputs unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended FARP1's receptor repertoire to the Neuropilin-1/PlexinA1 complex, establishing it as a Rac1 activator for Sema3A-induced dendritic arborization.\",\n      \"evidence\": \"Co-IP, knockdown and F-actin/dendritic morphometry in hippocampal neurons\",\n      \"pmids\": [\"24899721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FARP1 binds the receptor complex directly versus indirectly unresolved\", \"Domain mediating the interaction not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified FARP1 as a direct phosphorylation substrate of MAP4K4, introducing post-translational regulation of FARP1.\",\n      \"evidence\": \"Phosphoproteomics, in vitro kinase assay, Co-IP, neurite outgrowth assay in SH-SY5Y cells\",\n      \"pmids\": [\"26422651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of phosphorylation inferred, not tested via phospho-mutant FARP1\", \"Effect on GEF activity unknown\", \"pTL site role in localization undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Broadened FARP1's GTPase output, showing it activates Cdc42 in neuroendocrine cells rather than only Rho/Rac.\",\n      \"evidence\": \"siRNA knockdown and ELISA-based Cdc42 activity assay in PC12 cells\",\n      \"pmids\": [\"26911374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method for the FARP1-Cdc42 link\", \"Upstream receptor not identified\", \"Direct GEF activity toward Cdc42 not measured biochemically\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the structural basis for membrane targeting, showing the FERM domain's positively charged surface patch binds phospholipids and controls localization.\",\n      \"evidence\": \"X-ray crystallography of zebrafish FERM domain, lipid-binding assays, surface-patch mutants in cells/neurons\",\n      \"pmids\": [\"29992992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phospholipid species not fully defined\", \"How lipid binding integrates with receptor binding unresolved\", \"Full-length protein structure unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined FARP1 as a non-redundant Rac-GEF effector of RTK signaling in cancer cell migration, connecting it to the EGFR/c-Met–AXL–PI3K axis.\",\n      \"evidence\": \"RNAi screen, Rac1 activity assay, live imaging of ruffle dynamics, PI3K epistasis in lung cancer cells\",\n      \"pmids\": [\"34731623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical link between RTKs and FARP1 not established\", \"Mechanism of PI3K-dependent activation unclear\", \"Single cell-type/lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated evolutionary conservation of FARP1 function, placing the ortholog Cdep downstream of the Scribble/Dlg/Lgl polarity complex to drive collective migration.\",\n      \"evidence\": \"Genetic knockdown/rescue, GFP-relocalization rescue and epistasis in Drosophila border cells\",\n      \"pmids\": [\"36347240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical link between basolateral complex and Cdep unmapped\", \"Conservation of this pathway in mammalian FARP1 untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established FARP1 as a GPCR-coupled GEF, linking Gi/o receptors through a Gβγ/PKCα/Cdc42 axis to tunneling-nanotube formation.\",\n      \"evidence\": \"siRNA, pertussis toxin and biased-antagonist pharmacology, PI3K/PLCβ inhibition, Cdc42 activity assay in adrenocortical cancer cells\",\n      \"pmids\": [\"37390986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct activation of FARP1 by Gβγ or PKCα not biochemically shown\", \"Single cell model\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected FARP1 to metabolic regulation, showing the GPR81–FARP1–Rac1 axis drives insulin-independent GLUT4 translocation in muscle.\",\n      \"evidence\": \"Skeletal-muscle GPR81 knockout, ectopic expression, GLUT4 translocation and glucose tolerance assays\",\n      \"pmids\": [\"41530347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GPR81-FARP1 interaction not biochemically defined\", \"How FARP1 selects Rac1 here versus Cdc42 elsewhere unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirmed FARP1 as a c-Met Rac-GEF effector in a second cancer setting, showing HGF-induced PI3K-dependent recruitment to actin protrusions independent of VAV2.\",\n      \"evidence\": \"RNAi screen, Rac1 activity assay, FARP1 relocalization imaging, PI3K epistasis in prostate cancer cells\",\n      \"pmids\": [\"42175718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct c-Met–FARP1 binding not shown\", \"Mechanism of PI3K-dependent recruitment unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FARP1 integrates simultaneous lipid binding, receptor binding, and phosphorylation to select among RhoA, Rac1, and Cdc42 in a context-dependent manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length structure showing FERM-DH/PH autoregulation\", \"GTPase selectivity determinants undefined\", \"Direct receptor-binding interfaces beyond SynCAM 1 unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 3, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0007264\", \"supporting_discovery_ids\": [1, 3, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SynCAM 1\", \"PlexinA4\", \"Neuropilin-1\", \"PlexinA1\", \"MAP4K4\", \"GPR81\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}