Affinage

ARFGEF1

Brefeldin A-inhibited guanine nucleotide-exchange protein 1 · UniProt Q9Y6D6

Length
1849 aa
Mass
208.8 kDa
Annotated
2026-06-09
45 papers in source corpus 26 papers cited in narrative 26 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

ARFGEF1/BIG1 is a Golgi-localized guanine nucleotide exchange factor that activates class I ARFs via its Sec7 domain to drive vesicular trafficking, with brefeldin A acting as an uncompetitive inhibitor of the BIG1–ARF complex (PMID:10393931). It is recruited to the trans-Golgi by the Arf-like GTPase Arl1 binding its N-terminal region (PMID:22291037), downstream of a GEF cascade in which GBF1-activated ARF4/ARF5 promote BIG1/BIG2 TGN recruitment (PMID:23386609), where BIG1 acts redundantly with BIG2 in AP-1-dependent transport between the TGN and endosomes (PMID:18417613) while non-redundantly maintaining Golgi morphology (PMID:20360857). Through its GEF activity BIG1 controls surface trafficking of multiple cargoes, including integrin β1 glycosylation and RhoA activation (PMID:17227842), ABCA1 recycling and cholesterol efflux (PMID:23220274), and neuronal GABAA receptor surface expression (PMID:24198228). Its catalytic activity is subject to a cAMP/PKA switch: PKA phosphorylates Ser-883 to reduce GEF activity and is reversed by PP1γ (PMID:17360629), while PDE3A-containing AKAP complexes limit local cAMP to sustain ARF1 activation (PMID:19332778); the same phosphorylation, together with an NLS and intact microtubules, drives nuclear/nucleolar translocation where BIG1 associates with nucleolin, U3 snoRNA, and fibrillarin (PMID:16467138, PMID:18292223). Beyond catalysis, BIG1 scaffolds nonmuscle myosin IIA phosphatase complexes (with PP1δ and MYPT1) to regulate actomyosin dynamics and cell migration (PMID:23918382) and binds myosin IXb to inhibit its RhoA-GAP activity (PMID:15644318). In immune and neural contexts it promotes pro-inflammatory TLR4 signaling via ARF3-dependent PI(4,5)P2 synthesis and TIRAP recruitment (PMID:32415087), supports TNFR1 complex assembly through TRAF2 recruitment (PMID:27834853), and is required for Schwann cell myelination through ARF1/AP-1-dependent trafficking (PMID:29740613). Loss-of-function studies establish that BIG1 is essential for cortical neuron survival and axon guidance (PMID:28414797), and haploinsufficiency reduces seizure threshold via impaired GABAA receptor trafficking (PMID:31678406).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1999 High

    Established the core biochemical identity of BIG1 as a brefeldin-A-sensitive ARF guanine nucleotide exchange factor, answering what enzymatic activity the protein carries and where it acts.

    Evidence In vitro GTPγS loading assays with kinetic inhibition analysis and truncation mapping of the Golgi localization signal

    PMID:10393931

    Open questions at the time
    • Did not identify upstream recruiters or downstream trafficking cargoes
    • ARF isoform selectivity in vivo not resolved
  2. 2003 Medium

    Identified the first physical interaction partner (FKBP13) and linked immunophilin signaling to BIG1 membrane association.

    Evidence Yeast two-hybrid and reciprocal co-IP of endogenous proteins from Jurkat cells with GTPγS membrane-binding assay

    PMID:12606707

    Open questions at the time
    • Functional consequence of the BIG1–FKBP13 interaction unresolved
    • Single lab, no in vivo phenotype
  3. 2005 High

    Revealed a GEF-independent function by showing BIG1 directly inhibits myosin IXb RhoA-GAP activity, connecting BIG1 to Rho-GTPase regulation.

    Evidence Yeast two-hybrid, direct binding of purified proteins, GAP activity assay, endogenous co-IP

    PMID:15644318

    Open questions at the time
    • Cellular RhoA-pathway consequence not demonstrated in this study
    • Structural basis of competition with RhoA not defined
  4. 2004 Medium

    Demonstrated that BIG1 has a nuclear/nucleolar pool distinct from its Golgi ARF-activation role, since nuclear BIG1 lacked associated ARF but bound nucleolin and nucleoporin p62.

    Evidence Confocal microscopy, subcellular fractionation, and co-IP from purified nuclei of serum-starved HepG2 cells

    PMID:14973189

    Open questions at the time
    • Molecular function of nuclear BIG1 not established
    • Trigger for nuclear pool size not quantified
  5. 2006 High

    Defined the mechanism of nuclear translocation, showing PKA phosphorylation at Ser-883 plus a functional NLS and microtubule integrity are required.

    Evidence Site-directed mutagenesis of S883 and NLS, immunofluorescence, PKA inhibitors, and nocodazole treatment

    PMID:16467138

    Open questions at the time
    • Nuclear activity of translocated BIG1 not assayed
    • Identity of nuclear import machinery beyond NLS not defined
  6. 2007 High

    Connected the PKA phosphorylation switch to catalytic regulation, showing phosphorylation lowers GEF activity and PP1γ specifically reverses it.

    Evidence In vitro kinase, phosphatase, and GEF assays plus endogenous PP1γ co-IP from microsomes

    PMID:17360629

    Open questions at the time
    • Whether GEF inhibition and nuclear translocation are coupled or separable not resolved
    • Spatial coordination of the kinase/phosphatase not mapped
  7. 2007 Medium

    Linked BIG1 GEF function to a specific cargo pathway, showing it is required for integrin β1 glycosylation, RhoA activation, and cell migration, non-redundantly with BIG2.

    Evidence siRNA knockdown, glycosidase digestion, EM, RhoA pull-down, and overexpression rescue

    PMID:17227842

    Open questions at the time
    • Direct enzymatic step controlled by BIG1 in glycosylation not defined
    • Link between Golgi trafficking and RhoA activation mechanistically incomplete
  8. 2008 Medium

    Refined the nuclear function by placing BIG1 in nucleic-acid-dependent nucleolar complexes with nucleolin, U3 snoRNA, and fibrillarin.

    Evidence Co-IP from purified nuclei with RNase/DNase sensitivity and U3 snoRNA hybridization

    PMID:18292223

    Open questions at the time
    • Role in rRNA processing or ribosome biogenesis not tested
    • Whether GEF activity is involved in the nucleolus unknown
  9. 2007 Medium

    Established the structural basis for BIG-protein dimerization through DCB–DCB and DCB–HUS interactions, defining how the GEF self-associates.

    Evidence Yeast two-hybrid, in vitro biochemical interaction, and mammalian dimerization assays

    PMID:17640864

    Open questions at the time
    • Functional consequence of dimerization for GEF activity not quantified
    • Hetero- vs homodimer preference in vivo unresolved
  10. 2008 Medium

    Defined BIG1/BIG2 as redundant regulators of TGN–endosome trafficking acting in the AP-1 clathrin pathway, including furin retrograde transport.

    Evidence Double siRNA knockdown with trafficking readouts and AP-1 epistasis

    PMID:18417613

    Open questions at the time
    • Direct mechanistic link between ARF activation and AP-1 recruitment not shown here
    • Cargo specificity beyond furin not delineated
  11. 2009 Medium

    Showed that PDE3A-containing AKAP complexes sustain BIG1/BIG2 GEF activity by limiting local cAMP, integrating the PKA switch with localized signaling.

    Evidence siRNA and pharmacological PDE3A inhibition, confocal microscopy, and ARF1-GTP pull-down

    PMID:19332778

    Open questions at the time
    • Direct scaffolding architecture of the AKAP complex not resolved
    • In vivo relevance not tested
  12. 2010 Medium

    Distinguished a non-redundant role for BIG1 in maintaining Golgi morphology, separable from cargo export function.

    Evidence Comparative siRNA with fixed and live-cell Golgi imaging

    PMID:20360857

    Open questions at the time
    • Mechanism by which BIG1 maintains ribbon integrity unknown
    • Effector linking GEF activity to morphology not identified
  13. 2012 High

    Identified Arl1 as the direct recruiter of BIG1 to the trans-Golgi, answering how the GEF is targeted to membranes.

    Evidence Liposome affinity purification, Drosophila Sec71 binding, and Arl1 knockdown with localization readout across species

    PMID:22291037

    Open questions at the time
    • How Arl1 binding relates to PKA-regulated cytosolic/nuclear pools unresolved
    • Stoichiometry of recruitment not defined
  14. 2012 Medium

    Extended the GEF-dependent cargo repertoire to ABCA1, linking BIG1 to cholesterol efflux and lipid homeostasis.

    Evidence Vesicle co-IP, siRNA, surface biotinylation, cholesterol efflux assay, and GEF-dependent rescue

    PMID:23220274

    Open questions at the time
    • Direct vs indirect role of ARF1 on ABCA1 itinerary not fully separated
    • In vivo lipid phenotype not tested
  15. 2013 Medium

    Positioned BIG1/BIG2 downstream of GBF1 in a sequential GEF cascade, with GBF1-activated ARF4/ARF5 recruiting them to the TGN.

    Evidence Dominant-negative/activated ARF mutants, GBF1 depletion, and immunoelectron microscopy

    PMID:23386609

    Open questions at the time
    • Mechanistic coupling between ARF4/ARF5 and Arl1-mediated recruitment not integrated
    • Direct binding to ARF4/ARF5 not demonstrated
  16. 2013 High

    Established a catalysis-independent scaffolding role: BIG1/BIG2 assemble myosin IIA phosphatase complexes to control actomyosin dynamics and migration.

    Evidence Reciprocal endogenous co-IP, GEF-inactive C-terminal rescue, phospho-MLC blots, F-actin quantification, and migration assays

    PMID:23918382

    Open questions at the time
    • Direct binding interfaces within the phosphatase complex not mapped
    • Relationship to the myosin IXb interaction not integrated
  17. 2013 Medium

    Demonstrated that BIG1 GEF activity is required for neuronal GABAA receptor surface trafficking and chloride conductance.

    Evidence BIG1–GABAAR co-IP, siRNA, dominant-negative E793K, surface quantification, and Cl- influx electrophysiology

    PMID:24198228

    Open questions at the time
    • Trafficking step (forward vs recycling) not precisely localized
    • Subunit specificity of binding not fully defined
  18. 2013 Medium

    Linked BIG1 to neurite outgrowth through both GEF-dependent PI3K-AKT and partially GEF-independent ERK signaling.

    Evidence siRNA, BFA, dominant-negative and wild-type overexpression with phospho-pathway readouts and neurite measurements

    PMID:24090963

    Open questions at the time
    • How a GEF connects to ERK independent of catalysis unexplained
    • Direct signaling intermediates not identified
  19. 2016 Medium

    Connected BIG1 trafficking function to Wnt signaling by showing it binds β-catenin and controls its PKA-dependent S675 phosphorylation and transcriptional activity.

    Evidence Yeast two-hybrid, in vitro binding, co-IP, GEF-inactive mutants, reporter assays, and PLD dependence

    PMID:27162341

    Open questions at the time
    • Whether β-catenin is trafficking cargo or signaling partner not resolved
    • In vivo Wnt-pathway relevance untested
  20. 2016 Medium

    Implicated BIG1 in TNFR1 signaling by showing it is required for TRAF2 recruitment to complexes I and II and modulates JNK activation and apoptosis.

    Evidence siRNA, TNFR1 complex IP, TRAF2 ubiquitination assay, JNK blots, and apoptosis assays

    PMID:27834853

    Open questions at the time
    • Direct vs trafficking-mediated role in complex assembly unresolved
    • Whether GEF activity is required not tested
  21. 2017 Medium

    Demonstrated that BIG1 is essential in vivo for deep-layer cortical neuron survival, polarization, and axon guidance.

    Evidence Full BIG1 knockout mice with immunohistochemistry, migration assays, primary neuron polarization, and glutamate challenge

    PMID:28414797

    Open questions at the time
    • Molecular trafficking defect underlying neuron death not pinpointed
    • Cell-autonomy of axon guidance defects not fully separated
  22. 2018 High

    Defined the effector pathway for BIG1 in myelination, showing ARF1/AP-1-dependent (not GGA1 or COPI) trafficking is required for Schwann cell myelin formation.

    Evidence Schwann-cell-specific conditional KO of BIG1 and Arf1, EM, P0 immunofluorescence, and Arf1–adaptor co-IP

    PMID:29740613

    Open questions at the time
    • Specific myelin cargo trafficked via this pathway beyond P0 not enumerated
    • Generalizability to CNS myelination untested
  23. 2019 Medium

    Established the disease-relevant mechanism of haploinsufficiency, linking altered recycling endosome composition to reduced surface GABAA receptors and lowered seizure threshold.

    Evidence Heterozygous frameshift mouse, hippocampal neuron culture, endosome marker and surface GABAAR quantification, and PTZ seizure assay

    PMID:31678406

    Open questions at the time
    • Absence of spontaneous seizures leaves full human-phenotype recapitulation incomplete
    • Mechanism diverting GABAAR to lysosomes not detailed
  24. 2020 Medium

    Defined a pro-inflammatory signaling mechanism in which BIG1 activates ARF3 to drive PIP5K-mediated PI(4,5)P2 synthesis and TIRAP recruitment, amplifying TLR4 signaling in sepsis.

    Evidence Myeloid-specific conditional KO in LPS and CLP models, ARF3 activation, PI(4,5)P2 and TIRAP recruitment assays, and pathway blots

    PMID:32415087

    Open questions at the time
    • Spatial site of ARF3 activation (Golgi vs plasma membrane) not resolved
    • Whether ARF3 selectivity over ARF1 is intrinsic to BIG1 untested
  25. 2022 Medium

    Identified 14-3-3ζ as a regulator that stabilizes BIG1 surface expression and its interaction with GABAA receptors to control chloride conductance.

    Evidence In vitro and in vivo co-IP, siRNA, overexpression, surface quantification, and Cl- influx assay in hippocampal neurons

    PMID:36562883

    Open questions at the time
    • Whether 14-3-3ζ binding is phospho-dependent (e.g. via Ser-883) not tested
    • Mechanism of surface stabilization unresolved
  26. 2022 Medium

    Placed BIG1 downstream of KLF4 transcriptional control and within a PI3K/Akt/NF-κB axis driving microglial neuroinflammation.

    Evidence ChIP-qPCR, dual-luciferase reporter, siRNA, PI3K-agonist rescue, and migration/cytokine assays

    PMID:35090882

    Open questions at the time
    • Whether BIG1 GEF activity mediates the inflammatory phenotype not tested
    • Direct molecular link to NF-κB not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BIG1's distinct functional modes — Golgi GEF catalysis, GEF-independent scaffolding of myosin phosphatase, and nuclear/nucleolar association — are coordinated within a single protein, and what governs ARF-isoform selectivity across these contexts, remains unresolved.
  • No structural model integrating the catalytic, scaffolding, and nuclear functions
  • Mechanism of context-specific ARF1 vs ARF3 selection unknown
  • Direct nuclear molecular activity uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005794 Golgi apparatus 4 GO:0005634 nucleus 2 GO:0005635 nuclear envelope 2 GO:0005730 nucleolus 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2
Partners
ARF1ARL1CTNNB1FKBP13MYH9MYO9BTRAF2YWHAZ
Complex memberships
BIG1 homodimer/BIG-GBF1 dimer (DCB-HUS)PDE3A-containing AKAP complexmyosin phosphatase complex (myosin IIA / PP1δ / MYPT1)

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Human p200 ARF-GEP1 (ARFGEF1) is a Golgi-localized guanine nucleotide exchange factor whose Sec7 domain catalyzes GTP loading onto class I ARFs; brefeldin A acts as an uncompetitive inhibitor targeting the p200-ARF complex (Ki ~7 µM) rather than competing with ARF for p200 binding. Golgi localization signal maps to the N-terminal third of the protein. GTPγS loading assay (in vitro GEF activity), kinetic inhibition analysis, tagged-protein cellular localization by immunofluorescence, truncation mapping Proceedings of the National Academy of Sciences of the United States of America High 10393931
2003 The N-terminal region (aa 1–331) of BIG1 interacts with FK506-binding protein 13 (FKBP13); this association was confirmed by co-immunoprecipitation of endogenous BIG1 and FKBP13 from Jurkat T cells. FK506 treatment increased membrane binding of BIG1, BIG2, and ARF to Golgi and other membranes. Yeast two-hybrid screen, co-immunoprecipitation of endogenous proteins, in vitro membrane-binding assay with GTPγS Proceedings of the National Academy of Sciences of the United States of America Medium 12606707
2004 BIG1 localizes to nuclei (nuclear envelope/nucleoli) in serum-starved HepG2 cells independently of BIG2; nuclear BIG1 co-immunoprecipitates with nucleoporin p62 and nucleolin, but ARF is not detected in nuclear BIG1 immunoprecipitates, indicating independent nuclear functions distinct from Golgi ARF activation. Confocal immunofluorescence microscopy, subcellular fractionation, Western blot, co-immunoprecipitation from purified nuclei Proceedings of the National Academy of Sciences of the United States of America Medium 14973189
2005 BIG1 directly binds to the zinc finger/GAP domain of myosin IXb and inhibits myosin IXb RhoA-GAP activity (IC50 ~0.06 µM) by competing with RhoA for the same binding region on myosin IXb. Yeast two-hybrid, co-immunoprecipitation of endogenous proteins, in vitro direct binding with purified proteins, GAP activity assay The Journal of biological chemistry High 15644318
2006 PKA-catalyzed phosphorylation of BIG1 at Ser-883 is required for cAMP-induced nuclear accumulation of BIG1; a functional nuclear localization signal (712KPK714) is also necessary. Microtubule integrity (nocodazole-sensitive) is required for translocation. BIG2 is not similarly regulated. Site-directed mutagenesis (S883A, S883D, NLS mutant), immunofluorescence microscopy, PKA inhibitor (H-89, PKI) treatments, nocodazole treatment Proceedings of the National Academy of Sciences of the United States of America High 16467138
2007 PKA phosphorylates BIG1, significantly decreasing its GEF activity toward ARFs; protein phosphatase 1γ (but not PP1α, PP1β, or PP2A) reverses this phosphorylation and restores GEP activity. Endogenous PP1γ co-immunoprecipitates with BIG1 from microsomal fractions. Elevated cAMP induces PKA-catalyzed phosphorylation and nuclear accumulation of BIG1 but not BIG2. In vitro kinase assay with recombinant PKA, in vitro phosphatase assay with recombinant phosphatases, GEP activity assay from immunoprecipitated BIG1, co-immunoprecipitation, okadaic acid treatment Proceedings of the National Academy of Sciences of the United States of America High 17360629
2007 BIG1 is required for correct N-glycosylation of integrin β1 in the Golgi; BIG1 siRNA (but not BIG2 siRNA) causes aberrant electrophoretic mobility of β1, decreased active RhoA-GTP, impaired cell spreading, adhesion, and migration. Overexpression of HA-BIG1 restores RhoA-GTP levels. siRNA knockdown, PNGase F and EndoH glycosidase digestion, Western blot, electron microscopy (Golgi morphology), immunofluorescence, RhoA pull-down activity assay Proceedings of the National Academy of Sciences of the United States of America Medium 17227842
2007 BIG1 and BIG2 form homodimers through interactions between their conserved DCB domains; within each homodimer the DCB domain also interacts with the HUS domain via the HUS box. Both DCB and HUS domains are necessary for GBF1 dimerization in mammalian cells; the DCB domain is essential for yeast viability. Yeast two-hybrid assay, biochemical in vitro interaction assays, mammalian cell dimerization assay The Journal of biological chemistry Medium 17640864
2008 BIG1 in nuclei of HepG2 cells associates with nucleolin, U3 snoRNA, and fibrillarin, dependent on nucleic acids (RNase A/DNase-sensitive); BIG1 and nucleolin also associate with nucleoporin p62 at the nuclear envelope, suggesting BIG1 participates in dynamic nucleolar complexes. Co-immunoprecipitation from purified nuclei, RNase/DNase sensitivity experiments, 32P RNA labeling, U3 snoRNA-specific hybridization Proceedings of the National Academy of Sciences of the United States of America Medium 18292223
2008 BIG1 and BIG2 play redundant roles in membrane trafficking between the TGN and endosomes, including retrograde transport of furin from late endosomes to the TGN and maintenance of localization of TGN/recycling endosome proteins; this overlaps functionally with AP-1 clathrin adaptor activity. siRNA double knockdown (BIG1 and BIG2), immunofluorescence microscopy, protein localization assays, epistasis with AP-1 depletion Molecular biology of the cell Medium 18417613
2009 PDE3A interacts with BIG1 and BIG2 as part of AKAP complexes; depletion or inhibition of PDE3A disperses BIG1/BIG2 from the perinuclear Golgi and decreases membrane-associated ARF1-GTP, suggesting PDE3A limits local cAMP to prevent PKA-mediated inhibition of BIG1/BIG2 GEF activity. siRNA depletion of PDE3A, cilostamide pharmacological inhibition, confocal immunofluorescence, ARF1-GTP pull-down assay Proceedings of the National Academy of Sciences of the United States of America Medium 19332778
2010 BIG1 (but not BIG2) depletion causes fragmentation of the Golgi apparatus into mini-stacks that remain polarized and functional for cargo export, demonstrating a non-redundant role for BIG1 in maintaining normal Golgi morphology. siRNA knockdown, fixed and live-cell fluorescence imaging, Golgi morphology analysis PloS one Medium 20360857
2012 The Arf-like GTPase Arl1 directly binds the N-terminal region of BIG1/BIG2 (via their Drosophila ortholog Sec71) and is necessary for Golgi recruitment of BIG1 and BIG2 (but not GBF1) to the trans-Golgi in mammalian cells. Liposome-based affinity purification of Arl1 effectors, Drosophila Sec71 binding assay, mammalian Arl1 knockdown with BIG1/BIG2 localization readout The Journal of cell biology High 22291037
2012 BIG1 associates with ABCA1 in vesicle preparations from rat liver; BIG1 depletion reduces surface ABCA1, inhibits its internalization and recycling, and decreases cholesterol efflux by ~60%. These effects depend on BIG1 GEF activity and ARF1 activation. Vesicle immunoprecipitation, siRNA knockdown, surface biotinylation/glutathione cleavage assay, cholesterol efflux assay, BIG1 overexpression rescue Arteriosclerosis, thrombosis, and vascular biology Medium 23220274
2013 GBF1-activated ARF4 and ARF5 (but not ARF3) facilitate recruitment of BIG1 and BIG2 to the TGN, defining a functional GEF cascade where GBF1 at the TGN acts upstream of BIG1/BIG2 recruitment. GBF1 localizes ultrastructurally to pre-Golgi, Golgi, and TGN. Dominant-negative and activated ARF mutants, siRNA depletion of GBF1, immunofluorescence and immunoelectron microscopy for BIG1/BIG2 localization The Journal of biological chemistry Medium 23386609
2013 BIG1 and BIG2 form complexes with nonmuscle myosin IIA independently of their GEF catalytic activity (C-terminal sequences suffice for interaction); selective depletion of BIG1 or BIG2 enhances phosphorylation of myosin regulatory light chain (T18/S19) and F-actin content, impairing cell migration. BIG1/BIG2 scaffold myosin phosphatase complexes (including myosin IIA, PP1δ, and MYPT1) to regulate myosin IIA activity. Reciprocal co-immunoprecipitation of endogenous proteins, siRNA depletion, C-terminal rescue constructs (GEF-inactive), phospho-myosin light chain Western blot, F-actin quantification, Transwell migration assay Proceedings of the National Academy of Sciences of the United States of America High 23918382
2013 BIG1 directly binds GABAA receptor subunits and is required for their trafficking to the neuronal cell surface via its GEF activity; BIG1 depletion or dominant-negative BIG1-E793K expression reduces surface GABAAR and suppresses GABA-gated chloride influx. Co-immunoprecipitation (BIG1–GABAAR), siRNA knockdown, dominant-negative overexpression, surface GABAAR quantification, electrophysiology (Cl− influx assay) Molecular neurobiology Medium 24198228
2013 BIG1 GEF activity regulates neurite development via PI3K-AKT signaling (GEF-activity-dependent) and ERK signaling (partially GEF-activity-independent); BIG1 colocalizes with synaptophysin and its expression increases during rat brain development. siRNA knockdown, brefeldin A inhibition, dominant-negative BIG1 overexpression, wild-type BIG1 overexpression, phospho-Western blot for PI3K/AKT/ERK, neurite length measurement, immunostaining Neuroscience Medium 24090963
2016 BIG1 directly interacts with β-catenin via its N-terminal sequence; depletion of BIG1 and/or BIG2 or GEF-inactive mutant expression causes β-catenin accumulation at perinuclear Golgi and reduces PKA-phosphorylated β-catenin (S675). BIG2 AKAP-C sequence is required for PKA-mediated S675 phosphorylation and β-catenin transcription coactivator function. Effects require phospholipase D activity and vesicular trafficking. Yeast two-hybrid, in vitro synthesized protein binding, co-immunoprecipitation, siRNA depletion, GEF-inactive mutant, immunofluorescence, phospho-Western blot, transcriptional reporter assay Proceedings of the National Academy of Sciences of the United States of America Medium 27162341
2016 BIG1 is required for recruitment of TRAF2 to TNFR1 signaling complex (complex I) and to the death-inducing signaling complex (complex II) after TNF-α stimulation; BIG1 knockdown attenuates TNF-α-induced TRAF2 ubiquitination and JNK activation, and increases apoptosis sensitivity. siRNA knockdown, TNF-α stimulation, TNFR1 complex immunoprecipitation, TRAF2 ubiquitination assay, JNK activation Western blot, apoptosis assay International journal of molecular sciences Medium 27834853
2017 BIG1 loss in mice causes apoptosis of Tbr1+/Ctip2+ deep-layer neurons in a spatial-temporal pattern, impairs neuronal polarization in vitro, renders neurons hypersensitive to glutamate-induced apoptosis, and causes ectopic corticothalamic axon projections and failure of thalamocortical axons to cross the DTB. BIG1 knockout mouse (full KO), immunohistochemistry, pulse-chase migration assay, primary neuron culture, in vitro polarization assay, low-dose glutamate challenge PloS one Medium 28414797
2018 BIG1/Arfgef1 and its effector Arf1 are required for initiation of myelination by Schwann cells; Schwann cell-specific BIG1 conditional KO mice show reduced myelin thickness and decreased myelin protein zero (P0) in the myelin membrane. BIG1 KO specifically reduces Arf1 association with AP-1 clathrin adaptor subunits (but not GGA1 or COPI), indicating AP-1-dependent trafficking is the relevant effector pathway. Schwann cell-specific conditional KO mouse (BIG1 and Arf1), electron microscopy (myelin thickness), immunofluorescence (P0 localization), co-immunoprecipitation (Arf1 with AP-1, GGA1, COPI subunits), Western blot Science advances High 29740613
2019 Arfgef1 haploinsufficiency in mice alters neuronal endosome composition (altered ratio of Arf6+:Rab11+:TrfR+ recycling endosomes) and reduces dendritic surface and synaptic GABAA receptor levels (with increased lysosomal targeting), resulting in decreased seizure threshold but no spontaneous seizures. Heterozygous frameshift mouse model, primary hippocampal neuron culture, surface/synaptic GABAAR immunostaining, endosome marker quantification, pentylenetetrazol seizure threshold assay Neurobiology of disease Medium 31678406
2020 BIG1 promotes macrophage pro-inflammatory responses in sepsis via ARF3 activation, which stimulates PIP5K-mediated PI(4,5)P2 synthesis and TIRAP recruitment to the plasma membrane, thereby activating TLR4-MyD88 signaling. Myeloid-specific BIG1 cKO reduces sepsis mortality and organ damage. Myeloid-specific BIG1 conditional KO mouse (LPS and CLP models), bone marrow-derived macrophage cultures, ARF3 activation assay, PI(4,5)P2 measurement, TIRAP membrane recruitment assay, TLR4/MyD88/NF-κB pathway Western blot, cytokine ELISA Cell death & disease Medium 32415087
2022 14-3-3ζ interacts with both GABAA receptor β subunit and BIG1 in vitro and in vivo (hippocampal neurons); overexpression of 14-3-3ζ increases BIG1 surface expression and BIG1–GABAAR interaction, while 14-3-3ζ depletion reduces surface expression of both BIG1 and GABAAR and suppresses GABA-gated chloride influx. Co-immunoprecipitation (in vitro and in vivo), siRNA depletion, overexpression, immunofluorescence, surface expression quantification, Cl− influx assay Molecular neurobiology Medium 36562883
2022 KLF4 transcriptionally activates BIG1 (ARFGEF1) by binding its promoter (confirmed by ChIP-qPCR and dual-luciferase reporter assay); BIG1 mediates LPS-induced microglial neuroinflammation and migration via the PI3K/Akt/NF-κB pathway. ChIP-qPCR, dual-luciferase reporter assay, siRNA knockdown, PI3K agonist (740Y-P) rescue, RT-qPCR, ELISA, Transwell migration assay, Western blot Neuroscience Medium 35090882

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Overlapping and differential expression of BIG-2, BIG-1, TAG-1, and F3: four members of an axon-associated cell adhesion molecule subgroup of the immunoglobulin superfamily. Journal of neurobiology 142 8586965
1999 p200 ARF-GEP1: a Golgi-localized guanine nucleotide exchange protein whose Sec7 domain is targeted by the drug brefeldin A. Proceedings of the National Academy of Sciences of the United States of America 106 10393931
1994 BIG-1: a new TAG-1/F3-related member of the immunoglobulin superfamily with neurite outgrowth-promoting activity. Neuron 94 8060619
2008 Redundant roles of BIG2 and BIG1, guanine-nucleotide exchange factors for ADP-ribosylation factors in membrane traffic between the trans-Golgi network and endosomes. Molecular biology of the cell 75 18417613
2013 The Sec7 guanine nucleotide exchange factor GBF1 regulates membrane recruitment of BIG1 and BIG2 guanine nucleotide exchange factors to the trans-Golgi network (TGN). The Journal of biological chemistry 66 23386609
2012 The small G protein Arl1 directs the trans-Golgi-specific targeting of the Arf1 exchange factors BIG1 and BIG2. The Journal of cell biology 57 22291037
2022 The Novel KLF4/BIG1 Regulates LPS-mediated Neuro-inflammation and Migration in BV2 Cells via PI3K/Akt/NF-kB Signaling Pathway. Neuroscience 50 35090882
2015 MicroRNA-27b suppresses tumor progression by regulating ARFGEF1 and focal adhesion signaling. Cancer science 45 26473412
2007 Regulation of brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1) and BIG2 activity via PKA and protein phosphatase 1gamma. Proceedings of the National Academy of Sciences of the United States of America 45 17360629
2007 Interactions between conserved domains within homodimers in the BIG1, BIG2, and GBF1 Arf guanine nucleotide exchange factors. The Journal of biological chemistry 43 17640864
2019 miR-215 suppresses papillary thyroid cancer proliferation, migration, and invasion through the AKT/GSK-3β/Snail signaling by targeting ARFGEF1. Cell death & disease 42 30814512
2018 BIG1/Arfgef1 and Arf1 regulate the initiation of myelination by Schwann cells in mice. Science advances 38 29740613
2007 BIG1, a brefeldin A-inhibited guanine nucleotide-exchange protein, is required for correct glycosylation and function of integrin beta1. Proceedings of the National Academy of Sciences of the United States of America 38 17227842
2010 Specific functions of BIG1 and BIG2 in endomembrane organization. PloS one 37 20360857
2003 Interaction of FK506-binding protein 13 with brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1): effects of FK506. Proceedings of the National Academy of Sciences of the United States of America 35 12606707
2021 CircRNA ARFGEF1 functions as a ceRNA to promote oncogenic KSHV-encoded viral interferon regulatory factor induction of cell invasion and angiogenesis by upregulating glutaredoxin 3. PLoS pathogens 31 33539420
2017 MiR 376c inhibits osteoblastogenesis by targeting Wnt3 and ARF-GEF-1 -facilitated augmentation of beta-catenin transactivation. Journal of cellular biochemistry 31 29125885
2004 Nuclear localization and molecular partners of BIG1, a brefeldin A-inhibited guanine nucleotide-exchange protein for ADP-ribosylation factors. Proceedings of the National Academy of Sciences of the United States of America 28 14973189
2005 BIG1 is a binding partner of myosin IXb and regulates its Rho-GTPase activating protein activity. The Journal of biological chemistry 26 15644318
2013 Arf guanine nucleotide-exchange factors BIG1 and BIG2 regulate nonmuscle myosin IIA activity by anchoring myosin phosphatase complex. Proceedings of the National Academy of Sciences of the United States of America 25 23918382
2013 BIG1, a brefeldin A-inhibited guanine nucleotide-exchange protein regulates neurite development via PI3K-AKT and ERK signaling pathways. Neuroscience 24 24090963
2009 Interaction of phosphodiesterase 3A with brefeldin A-inhibited guanine nucleotide-exchange proteins BIG1 and BIG2 and effect on ARF1 activity. Proceedings of the National Academy of Sciences of the United States of America 24 19332778
2012 BIG1, a brefeldin A-inhibited guanine nucleotide-exchange protein modulates ATP-binding cassette transporter A-1 trafficking and function. Arteriosclerosis, thrombosis, and vascular biology 21 23220274
2020 BIG1 controls macrophage pro-inflammatory responses through ARF3-mediated PI(4,5)P2 synthesis. Cell death & disease 20 32415087
2016 Enhancement of β-catenin activity by BIG1 plus BIG2 via Arf activation and cAMP signals. Proceedings of the National Academy of Sciences of the United States of America 20 27162341
2008 Association of guanine nucleotide-exchange protein BIG1 in HepG2 cell nuclei with nucleolin, U3 snoRNA, and fibrillarin. Proceedings of the National Academy of Sciences of the United States of America 20 18292223
2011 Downregulation of ARFGEF1 and CAMK2B by promoter hypermethylation in breast cancer cells. BMB reports 19 21871176
2006 Effect of protein kinase A on accumulation of brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1) in HepG2 cell nuclei. Proceedings of the National Academy of Sciences of the United States of America 19 16467138
2016 Brefeldin A-Inhibited Guanine Nucleotide-Exchange Factor 1 (BIG1) Governs the Recruitment of Tumor Necrosis Factor Receptor-Associated Factor 2 (TRAF2) to Tumor Necrosis Factor Receptor 1 (TNFR1) Signaling Complexes. International journal of molecular sciences 16 27834853
2021 Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity. Genetics in medicine : official journal of the American College of Medical Genetics 15 34113008
2021 BIG1 mediates sepsis-induced lung injury by modulating lipid raft-dependent macrophage inflammatory responses. Acta biochimica et biophysica Sinica 15 34153089
2021 Circ_0059354 aggravates the progression of papillary thyroid carcinoma by elevating ARFGEF1 through sponging miR-766-3p. Journal of endocrinological investigation 14 34854069
2005 BIG1 and BIG2, brefeldin A-inhibited guanine nucleotide-exchange factors for ADP-ribosylation factors. Methods in enzymology 14 16413268
2019 Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors. Neurobiology of disease 11 31678406
2017 BIG1 is required for the survival of deep layer neurons, neuronal polarity, and the formation of axonal tracts between the thalamus and neocortex in developing brain. PloS one 11 28414797
2022 The miR-133b/brefeldin A-inhibited guanine nucleotide-exchange protein 1 (ARFGEF1) axis represses proliferation, invasion, and migration in cervical cancer cells. Bioengineered 9 35048795
2019 Involvement of BIG1 and BIG2 in regulating VEGF expression and angiogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 9 31199673
2013 BIG1, a brefeldin A-inhibited guanine nucleotide-exchange factor, is required for GABA-gated Cl⁻ influx through regulation of GABAA receptor trafficking. Molecular neurobiology 9 24198228
2022 Expanding the Phenotypic and Genotypic Spectrum of ARFGEF1-Related Neurodevelopmental Disorder. Frontiers in molecular neuroscience 3 35782386
2022 14-3-3ζ Mediates GABAAR Activation by Interacting with BIG1. Molecular neurobiology 3 36562883
2024 Big1 is a newly identified autophagy regulator that is critical for a fully functional V-ATPase. Molecular biology of the cell 2 39259764
2026 Distinct membrane trafficking pathways defined by the requirement for GNOM or BIG1 to BIG4 mediate preinvasive immunity toward filamentous fungal pathogens. The New phytologist 1 41574444
2026 Big1 is a cell-cycle regulator linking cell size to basal body number in Tetrahymena thermophila. Current biology : CB 0 41875877
2026 Correction: CircRNA ARFGEF1 functions as a ceRNA to promote oncogenic KSHV-encoded viral interferon regulatory factor induction of cell invasion and angiogenesis by upregulating glutaredoxin 3. PLoS pathogens 0 42201909
2025 Big1 is a cell cycle regulator linking cell size to basal body number. bioRxiv : the preprint server for biology 0 40777362

Missed literature

Know a paper Affinage missed for ARFGEF1? Flag it for the maintainers and the community.

No submissions yet.