Affinage

FARP1

FERM, ARHGEF and pleckstrin domain-containing protein 1 · UniProt Q9Y4F1

Length
1045 aa
Mass
118.6 kDa
Annotated
2026-06-09
22 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1997 Medium

    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

    PMID:9425278

    Open questions at the time
    • No biochemical demonstration of GEF activity
    • GTPase specificity undefined
    • No cellular or in vivo function tested
  2. 2001 High

    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

    PMID:11680691

    Open questions at the time
    • RhoA tested in vitro but physiological substrate in cells unresolved
    • Upstream activating signals unknown
    • Role of FERM domain not addressed
  3. 2009 High

    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

    PMID:19217374

    Open questions at the time
    • Direct biochemical link between PlexinA4 and FARP1 not shown
    • Which GTPase is activated in this context unspecified
    • Mechanism of retinoid-induced expression not detailed
  4. 2012 High

    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

    PMID:23209303

    Open questions at the time
    • Structural basis of FERM-SynCAM 1 binding not resolved
    • Mechanism of retrograde signal transmission incomplete
    • Relationship to plexin pathway inputs unclear
  5. 2014 High

    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

    PMID:24899721

    Open questions at the time
    • Whether FARP1 binds the receptor complex directly versus indirectly unresolved
    • Domain mediating the interaction not mapped
  6. 2015 Medium

    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

    PMID:26422651

    Open questions at the time
    • Functional consequence of phosphorylation inferred, not tested via phospho-mutant FARP1
    • Effect on GEF activity unknown
    • pTL site role in localization undefined
  7. 2016 Medium

    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

    PMID:26911374

    Open questions at the time
    • Single method for the FARP1-Cdc42 link
    • Upstream receptor not identified
    • Direct GEF activity toward Cdc42 not measured biochemically
  8. 2018 High

    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

    PMID:29992992

    Open questions at the time
    • Specific phospholipid species not fully defined
    • How lipid binding integrates with receptor binding unresolved
    • Full-length protein structure unknown
  9. 2021 Medium

    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

    PMID:34731623

    Open questions at the time
    • Direct physical link between RTKs and FARP1 not established
    • Mechanism of PI3K-dependent activation unclear
    • Single cell-type/lab
  10. 2022 High

    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

    PMID:36347240

    Open questions at the time
    • Biochemical link between basolateral complex and Cdep unmapped
    • Conservation of this pathway in mammalian FARP1 untested
  11. 2023 Medium

    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

    PMID:37390986

    Open questions at the time
    • Direct activation of FARP1 by Gβγ or PKCα not biochemically shown
    • Single cell model
  12. 2026 Medium

    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

    PMID:41530347

    Open questions at the time
    • Direct GPR81-FARP1 interaction not biochemically defined
    • How FARP1 selects Rac1 here versus Cdc42 elsewhere unresolved
  13. 2026 Medium

    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

    PMID:42175718

    Open questions at the time
    • Direct c-Met–FARP1 binding not shown
    • Mechanism of PI3K-dependent recruitment unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FARP1 integrates simultaneous lipid binding, receptor binding, and phosphorylation to select among RhoA, Rac1, and Cdc42 in a context-dependent manner remains unresolved.
  • No full-length structure showing FERM-DH/PH autoregulation
  • GTPase selectivity determinants undefined
  • Direct receptor-binding interfaces beyond SynCAM 1 unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0008092 cytoskeletal protein binding 2 GO:0060089 molecular transducer activity 2 GO:0008289 lipid binding 1
Localization
GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 1
Partners
GPR81MAP4K4NEUROPILIN-1PLEXINA1PLEXINA4SYNCAM 1

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 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. cDNA cloning, sequence analysis Biochemical and biophysical research communications Medium 9425278
2001 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. In vitro [3H]GDP dissociation assay using recombinant DH/PH domain peptide from Sf9 cells; NIH3T3 focus-formation assay Osteoarthritis and cartilage High 11680691
2009 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. In vivo loss-of-function and gain-of-function in chick spinal cord; dominant-negative and domain-deletion constructs; morphometric analysis of dendritic arbors Neuron High 19217374
2012 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. 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 The Journal of cell biology High 23209303
2014 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. Co-immunoprecipitation; knockdown in hippocampal neurons; F-actin imaging; dendritic morphometry; pharmacological silencing (TTX) and proteasome inhibition The Journal of neuroscience High 24899721
2015 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. Phosphoproteomic profiling of MAP4K4 inhibition; in vitro kinase assay; co-immunoprecipitation; neurite outgrowth assay ACS chemical biology Medium 26422651
2016 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. siRNA knockdown; ELISA-based Cdc42 activity assay Endocrine-related cancer Medium 26911374
2018 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. X-ray crystallography; in vitro lipid-binding assay; cell-based membrane localization assay with surface-patch mutants; neuronal imaging Scientific reports High 29992992
2019 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. siRNA knockdown; Western blot for pMEK/MEK and pERK/ERK; CCK8 proliferation assay; wound-healing and Transwell invasion assays The American Journal of dermatopathology Low 31021836
2021 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. RNAi screen; siRNA knockdown; Rac1 activity assay; live-cell imaging of ruffle dynamics; migration assays; epistasis with PI3K inhibition Cell reports Medium 34731623
2022 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. Genetic knockdown/rescue in Drosophila border cells; live imaging; GFP-fusion relocalization rescue experiment; epistasis analysis with Scribble, Dlg, Lgl Developmental cell High 36347240
2023 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. siRNA knockdown; pertussis toxin and biased antagonist pharmacology; PI3K and PLCβ inhibition; Cdc42 activity assay; live-cell imaging of TNT structures The Journal of biological chemistry Medium 37390986
2026 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. Genetic knockout of GPR81 in skeletal muscle; ectopic expression; pharmacological GPR81 activation; GLUT4 translocation assay; glucose tolerance test; mechanistic pathway analysis Cell research Medium 41530347
2026 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. Unbiased RNAi screen targeting Rac-GEFs; siRNA knockdown; Rac1 activity assay; live-cell imaging of actin protrusions; PI3K inhibition epistasis; migration and invasion assays Endocrinology Medium 42175718

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 LncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc. Nature communications 284 31375671
2010 Selective isolation of live/dead cells using contactless dielectrophoresis (cDEP). Lab on a chip 179 20126683
2012 The novel synaptogenic protein Farp1 links postsynaptic cytoskeletal dynamics and transsynaptic organization. The Journal of cell biology 91 23209303
2009 FARP1 promotes the dendritic growth of spinal motor neuron subtypes through transmembrane Semaphorin6A and PlexinA4 signaling. Neuron 78 19217374
2014 Activity-dependent regulation of dendritic complexity by semaphorin 3A through Farp1. The Journal of neuroscience : the official journal of the Society for Neuroscience 46 24899721
1997 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. Biochemical and biophysical research communications 31 9425278
2021 FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma. Cell reports 30 34731623
2016 Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression. Endocrine-related cancer 24 26911374
2022 A Scribble/Cdep/Rac pathway controls follower-cell crawling and cluster cohesion during collective border-cell migration. Developmental cell 19 36347240
2018 Structural analyses of FERM domain-mediated membrane localization of FARP1. Scientific reports 15 29992992
2023 Gi/o GPCRs drive the formation of actin-rich tunneling nanotubes in cancer cells via a Gβγ/PKCα/FARP1/Cdc42 axis. The Journal of biological chemistry 14 37390986
2015 MAP4K4 Is a Threonine Kinase That Phosphorylates FARP1. ACS chemical biology 14 26422651
2001 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. Osteoarthritis and cartilage 14 11680691
2020 FARP-1 deletion is associated with lack of response to autism treatment by early start denver model in a multiplex family. Molecular genetics & genomic medicine 11 32588496
2021 An oncogenic lncRNA, GLCC1, promotes tumorigenesis in gastric carcinoma by enhancing the c-Myc/IGF2BP1 interaction. Neoplasma 7 34196212
2017 Alternative cDEP Design to Facilitate Cell Isolation for Identification by Raman Spectroscopy. Sensors (Basel, Switzerland) 7 28208767
2011 Consistent Differential Expression Pattern (CDEP) on microarray to identify genes related to metastatic behavior. BMC bioinformatics 7 22078224
2002 [Cloning and characterization of cuticle degrading enzyme CDEP-1 from Beauveria bassiana]. Yi chuan xue bao = Acta genetica Sinica 5 12182086
2019 FARP1 Facilitates Cell Proliferation Through Modulating MAPK Signaling Pathway in Cutaneous Melanoma. The American Journal of dermatopathology 4 31021836
2026 Lactate-activated GPR81/FARP1 signaling drives insulin-independent glucose uptake and metabolic control. Cell research 1 41530347
2024 Conserved region of human TDP-43 is structurally similar to membrane binding protein FARP1 and protein chaperons BAG6 and CYP33. microPublication biology 1 39583578
2026 FARP1 mediates cMET-driven motility in androgen-independent prostate cancer cells. Endocrinology 0 42175718

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