Affinage

Showing ARFGEF2 — BIG2 is a alias.

ARFGEF2

Brefeldin A-inhibited guanine nucleotide-exchange protein 2 · UniProt Q9Y6D5

Length
1785 aa
Mass
202.0 kDa
Annotated
2026-06-09
40 papers in source corpus 24 papers cited in narrative 24 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

ARFGEF2 (BIG2) is a brefeldin A-sensitive guanine nucleotide exchange factor that activates class I ARFs (ARF1 and ARF3) to drive membrane trafficking at the trans-Golgi network (TGN) and recycling endosomes, and through this activity it controls cargo delivery, organelle integrity, and several downstream signaling outputs (PMID:14647276, PMID:15385626). By activating ARFs at the TGN, BIG2 recruits the clathrin adaptors AP-1 and GGA — but not the COPI coat — placing it specifically in the TGN-to-endosome arm of membrane traffic, and it acts redundantly with its homolog BIG1 in AP-1-dependent retrograde transport while retaining a non-redundant role in maintaining recycling endosome integrity (PMID:11777925, PMID:12051703, PMID:18417613, PMID:20360857). Its catalytic activity is required for recycling of cargoes including the transferrin receptor and integrin beta1, and for release of TNFR1 exosome-like vesicles, and BIG2 transports E-cadherin, beta-catenin, and Filamin A from the Golgi to the cell surface (PMID:14647276, PMID:15385626, PMID:16477018, PMID:16320251, PMID:17276987, PMID:22908276). BIG2 is recruited to the TGN by the small G protein Arl1 acting downstream of a GBF1→ARF4/ARF5 cascade, and it homodimerizes through an intramolecular DCB/HUS interaction (PMID:22291037, PMID:23386609, PMID:17640864). Beyond catalysis, BIG2 functions as an A-kinase-anchoring protein (AKAP) with three N-terminal domains that bind PKA regulatory subunits; PKA phosphorylation lowers its GEF activity and is reversed by PP1gamma, and this AKAP/cAMP module — also engaging PDE3A — couples BIG2 to TNFR1 vesicle release and beta-catenin S675 phosphorylation and transcriptional coactivation (PMID:12571360, PMID:17360629, PMID:18625701, PMID:19332778, PMID:27162341). BIG2 additionally scaffolds a myosin phosphatase complex (myosin IIA, PP1delta, MYPT1) independently of its GEF activity to control myosin light-chain phosphorylation, F-actin content, and cell migration, and drives a BIG2-ARF1-RhoA-mDia1 axis governing dendritic Golgi polarization in neurons (PMID:23918382, PMID:29455446). BIG2 is also required for VEGF expression and angiogenesis (PMID:31199673).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2002 Medium

    Established that BIG2 selectively controls the membrane association of the AP-1/GGA clathrin adaptors at the TGN rather than the COPI coat, defining which trafficking step it serves.

    Evidence BIG2 overexpression and dominant-negative mutant expression with immunofluorescence redistribution of ARF1, AP-1, GGA1, and COPI in cells

    PMID:11777925 PMID:12051703

    Open questions at the time
    • Did not establish direct catalytic GEF activity toward specific ARF isoforms
    • Cargo specificity of the AP-1/GGA pathway not defined
  2. 2003 High

    Showed BIG2-dependent TGN trafficking is needed for neural progenitor proliferation and for surface delivery of E-cadherin and beta-catenin, linking the GEF to a physiological/developmental output.

    Evidence Dominant-negative cDNA, brefeldin A inhibition, proliferation and immunolocalization assays in cultured cells

    PMID:14647276

    Open questions at the time
    • Did not resolve direct vs indirect effect on cargo transport
    • ARF isoform specificity not addressed
  3. 2003 High

    Identified BIG2 as an AKAP with three mapped PKA-regulatory-subunit-binding domains whose membrane recruitment responds to cAMP, defining a non-catalytic scaffolding function.

    Evidence Yeast two-hybrid, reciprocal Co-IP of endogenous proteins, 28 deletion mutants, subcellular fractionation with cAMP elevation

    PMID:12571360

    Open questions at the time
    • Did not show how PKA anchoring feeds back on GEF activity
    • Functional consequence of cAMP-induced translocation not established
  4. 2004 High

    Defined BIG2 catalytic specificity toward class I ARFs (ARF1/ARF3) and demonstrated via active-site mutagenesis and ARF epistasis that it maintains recycling endosome integrity.

    Evidence Catalytically inactive E738K mutant, ARF1/ARF3 inactivation epistasis, localization in cells

    PMID:15385626

    Open questions at the time
    • Mechanism distinguishing TGN vs recycling endosome pools not resolved
    • Recruitment determinants to each compartment not defined
  5. 2005 Medium

    Linked BIG2 to the exocyst by identifying an N-terminal Exo70 interaction and shared TGN/centrosomal localization, extending its reach toward plasma-membrane-directed traffic.

    Evidence Yeast two-hybrid, Co-IP of in vitro translated proteins, confocal microscopy, centrosome purification in HepG2 cells

    PMID:15705715

    Open questions at the time
    • Functional consequence of Exo70 binding not tested
    • Endogenous interaction not confirmed in this study
  6. 2006 High

    Demonstrated a non-redundant, BIG2-specific role (distinct from BIG1) in transferrin receptor recycling and in trafficking the cytoskeletal cargo Filamin A, plus TGN anchoring of AMY-1.

    Evidence siRNA knockdown with transferrin recycling assay and density-gradient fractionation; dominant-negative FLNA trafficking assay; reciprocal Co-IP and RNAi for AMY-1 localization

    PMID:16320251 PMID:16477018 PMID:16866877

    Open questions at the time
    • Molecular basis for BIG2 vs BIG1 cargo discrimination unresolved
    • Direct GEF-cargo coupling not established
  7. 2007 High

    Connected BIG2 GEF activity to a secretory output (TNFR1 exosome-like vesicle release) via nonredundant ARF1/ARF3 action, and established the PKA/PP1gamma phosphoregulatory loop controlling BIG2 catalysis.

    Evidence Isoform-specific siRNA with TNFR1 release assay and BFA disruption; in vitro PKA phosphorylation/GEP activity assay, recombinant PP1 isoform treatment, endogenous Co-IP

    PMID:17276987 PMID:17360629

    Open questions at the time
    • In vivo relevance of PKA/PP1gamma regulation not shown
    • Site of phosphorylation on BIG2 not mapped
  8. 2007 Medium

    Defined the structural basis of BIG2 self-association through DCB-mediated homodimerization and an intramolecular DCB/HUS interaction.

    Evidence Yeast two-hybrid, biochemical interaction and deletion-mutant analysis, cellular dimerization assays

    PMID:17640864

    Open questions at the time
    • No structural model of the dimer
    • Functional requirement of dimerization for GEF activity untested
  9. 2008 Medium

    Established BIG2/BIG1 redundancy in AP-1-dependent retrograde furin transport and showed cAMP-induced TNFR1 vesicle release operates through BIG2 AKAP domains binding RIIbeta.

    Evidence RNAi double knockdown with furin localization vs AP-1 depletion comparison; PKA subunit siRNA, TNFR1 release assay, AKAP domain mapping

    PMID:18417613 PMID:18625701

    Open questions at the time
    • Degree of redundancy across cargoes not generalized
    • Mechanism coupling AKAP-bound PKA to ARF activation incomplete
  10. 2009 Medium

    Placed PDE3A within BIG2 AKAP complexes as a cAMP-degrading regulator required for membrane association of BIG2 and ARF1 activation.

    Evidence PDE3A siRNA and cilostamide inhibition, confocal microscopy, ARF1-GTP measurement

    PMID:19332778

    Open questions at the time
    • Direct vs indirect PDE3A-BIG2 interaction not resolved
    • Cargo-level consequences not measured
  11. 2010 Medium

    Distinguished non-redundant morphological roles: BIG2 depletion tubulates recycling endosomes while BIG1 depletion fragments the Golgi.

    Evidence siRNA knockdown with fixed and live-cell imaging of Golgi and endosomal markers

    PMID:20360857

    Open questions at the time
    • Molecular determinants of compartment-specific action unknown
  12. 2012 High

    Identified Arl1 as the upstream small G protein necessary and sufficient to recruit BIG2 to the TGN, defining how the GEF is targeted to its compartment.

    Evidence Liposome-based affinity purification, Arl1 knockdown in mammalian cells, Drosophila Sec71 ortholog binding, immunofluorescence

    PMID:22291037

    Open questions at the time
    • How Arl1 recruitment is itself initiated unresolved at this step
    • Recycling endosome recruitment mechanism not addressed
  13. 2012 Medium

    Extended BIG2's recycling function to integrin beta1 and linked it to actin dynamics and cell motility through proteomic and migration readouts.

    Evidence siRNA knockdown, DIGE proteomics, integrin beta1 trafficking and wound-healing migration assays

    PMID:22908276

    Open questions at the time
    • Direct mechanism connecting integrin recycling to actin regulators not defined
    • GEF dependence of the migration phenotype not isolated
  14. 2013 High

    Positioned BIG2 in a GEF cascade (GBF1→ARF4/ARF5→BIG2 recruitment) and revealed a GEF-independent scaffolding role anchoring a myosin phosphatase complex that controls actomyosin and migration.

    Evidence GBF1 dominant-negative and ARF-isoform depletion with immuno-EM; reciprocal endogenous Co-IP of myosin IIA, siRNA, phospho-MLC and F-actin assays, Transwell migration, C-terminal rescue

    PMID:23386609 PMID:23918382

    Open questions at the time
    • How catalytic and scaffolding functions are coordinated within one molecule unclear
    • Structural basis of myosin phosphatase anchoring not defined
  15. 2016 Medium

    Connected BIG2 trafficking and AKAP function to beta-catenin biology, showing it controls beta-catenin Golgi exit, PKA-dependent S675 phosphorylation, and transcriptional coactivation.

    Evidence Co-IP, yeast two-hybrid, siRNA, GEF-inactive mutants, phospho-beta-catenin Western blot, transcription reporter assays

    PMID:27162341

    Open questions at the time
    • Direct vs trafficking-mediated effect on beta-catenin phosphorylation not fully separated
    • Target gene specificity not mapped
  16. 2018 Medium

    Defined a neuronal BIG2-ARF1-RhoA-mDia1 axis required for dendritic Golgi polarization and dendrite growth, validated in vivo.

    Evidence shRNA knockdown, ARF1 Q71L and LPA rescue, RhoA activation assay, immunofluorescence, in utero electroporation in mouse

    PMID:29455446

    Open questions at the time
    • How ARF1 activates RhoA mechanistically not resolved
    • Behavioral/developmental consequences not assessed
  17. 2019 Medium

    Revealed a role for BIG2 in VEGF expression and angiogenesis, extending its function beyond intracellular trafficking, with in vivo zebrafish validation.

    Evidence siRNA, VEGF mRNA/protein quantification, HUVEC migration/angiogenesis assays, zebrafish morpholino and CRISPR/Cas9 deletion with vascular imaging

    PMID:31199673

    Open questions at the time
    • Mechanism linking BIG2 to VEGF transcription not defined
    • Whether the angiogenesis role is GEF-dependent unclear
  18. 2025 Medium

    Showed in a Drosophila ortholog context that Arf1/Sec71 anchor cortical myosin II during asymmetric neuroblast division by directing PI(4)P localization, linking lipid production to actomyosin organization.

    Evidence Drosophila genetic epistasis, Co-IP of Arf1 with Sqh and Vibrator, PI(4)P and myosin II cortical imaging, loss-of-function division assays

    PMID:40208939

    Open questions at the time
    • Conservation of the PI(4)P-myosin mechanism in mammalian ARFGEF2 not tested
    • Direct ARFGEF2 (vs Arf1) requirement in this lipid pathway not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BIG2 integrates its catalytic ARF-GEF activity, AKAP/cAMP phosphoregulation, and GEF-independent myosin phosphatase scaffolding into a single coordinated program across distinct compartments and cell types remains unresolved.
  • No integrated structural model of full-length BIG2 with its partners
  • Mechanism switching BIG2 between catalytic and scaffolding modes unknown
  • In vivo relevance of most regulatory loops not established in mammals

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005768 endosome 3 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-9609507 Protein localization 4 R-HSA-162582 Signal Transduction 3
Partners
ARF1ARF3ARL1CTNNB1 (BETA-CATENIN)EXO70MYH9 (NONMUSCLE MYOSIN IIA)PDE3APPP1CC (PP1GAMMA)
Complex memberships
BIG2 AKAP-PKA complexmyosin phosphatase complex (myosin IIA / PP1delta / MYPT1)

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 ARFGEF2/BIG2 is required for vesicle and membrane trafficking from the trans-Golgi network (TGN); inhibition by brefeldin A or dominant-negative ARFGEF2 cDNA decreases neural progenitor cell proliferation in vitro and disrupts intracellular localization of E-cadherin and beta-catenin by preventing their transport from the Golgi apparatus to the cell surface. Dominant-negative cDNA expression, brefeldin A inhibition, cell proliferation assays, immunofluorescence localization of E-cadherin and beta-catenin in cultured cells Nature genetics High 14647276
2002 BIG2 overexpression blocks BFA-induced redistribution of ARF1 and the AP-1 complex from TGN membranes but not the COPI complex, indicating BIG2 specifically regulates membrane association of AP-1 (but not COPI) through ARF activation at the TGN. Overexpression of BIG2 in cells, BFA treatment, immunofluorescence redistribution assays for ARF1, AP-1, and COPI coat proteins The Journal of biological chemistry Medium 11777925
2002 A dominant-negative BIG2 mutant induces redistribution of AP-1 and GGA1 coat proteins and membrane tubulation of the TGN, but does not affect COPI redistribution or Golgi tubulation, placing BIG2 specifically in the TGN-to-endosome trafficking pathway via AP-1 and GGA regulation. Dominant-negative BIG2 mutant expression, immunofluorescence for AP-1, GGA1, COPI, organelle markers Biochemical and biophysical research communications Medium 12051703
2004 BIG2 localizes to both the TGN and recycling endosomes; expression of a catalytically inactive BIG2 mutant (E738K) selectively induces membrane tubules from the recycling endosome compartment. BIG2 has exchange activity toward class I ARFs (ARF1 and ARF3) in vivo, and inactivation of either ARF exaggerates tubulation induced by BIG2(E738K), indicating BIG2 maintains recycling endosome integrity via class I ARF activation. Catalytically inactive mutant (E738K) expression, immunofluorescence, ARF1/ARF3 inactivation epistasis, subcellular fractionation/localization Molecular biology of the cell High 15385626
2003 BIG2 contains three A kinase-anchoring protein (AKAP) domains in its N-terminal region: domain A (residues 27–48) interacts with RI-alpha and RI-beta; domain B (284–301) interacts with RII-alpha and RII-beta; domain C (517–538) interacts with RI-alpha, RII-alpha, and RII-beta. BIG2 physically interacts with the PKA regulatory subunit RI-alpha, confirmed by coimmunoprecipitation of in vitro translated proteins and endogenous proteins. Elevation of cAMP (8-Br-cAMP or forskolin) induces translocation of BIG2 from cytosol to Golgi and other membranes. Yeast two-hybrid screen, coimmunoprecipitation of in vitro translated and endogenous proteins, 28 deletion mutants, Western blot subcellular fractionation Proceedings of the National Academy of Sciences of the United States of America High 12571360
2005 BIG2 physically interacts with exocyst protein Exo70 via its N-terminal region (amino acids 1–643); both BIG2 and Exo70 co-localize at trans-Golgi network membranes and at the microtubule-organizing center (MTOC)/centrosomes in HepG2 cells, suggesting functional association in vesicular trafficking from TGN to plasma membrane. Yeast two-hybrid screen, coimmunoprecipitation of in vitro translated proteins, immunofluorescence confocal microscopy, centrosome purification Proceedings of the National Academy of Sciences of the United States of America Medium 15705715
2006 BIG2 localizes specifically (not BIG1) to recycling endosome structures during transferrin uptake and transferrin receptor (TfnR) recycling in COS7 cells. BIG2 siRNA knockdown causes perinuclear accumulation of TfnR and significantly slows transferrin release, demonstrating a functional role for BIG2 in TfnR recycling. BIG2 interacts with Exo70 in recycling endosome fractions. Immunofluorescence microscopy, density-gradient fractionation, siRNA knockdown, transferrin recycling assay Proceedings of the National Academy of Sciences of the United States of America High 16477018
2006 BIG2 (but not BIG1) is required for trafficking of Filamin A (FLNA) from the Golgi apparatus to the cell membrane in neuroblastoma cells; transfection of dominant-negative ARFGEF2 partially blocks FLNA transport. BIG2 and FLNA are co-expressed in neural progenitors along the neuroependyma. Dominant-negative ARFGEF2 transfection, immunofluorescence for FLNA localization, Western blot co-expression The Journal of comparative neurology Medium 16320251
2007 BIG2 (not BIG1) regulates constitutive release of TNFR1 exosome-like vesicles from human vascular endothelial cells via an ARF1- and ARF3-dependent mechanism. BIG2 co-localizes with TNFR1 in cytoplasmic vesicles, and this association is disrupted by BFA. ARF1 and ARF3 act nonredundantly and additively in TNFR1 exosome-like vesicle release. RNA interference (specific siRNA for BIG1, BIG2, ARF1, ARF3), TNFR1 release assay, immunofluorescence co-localization, BFA disruption The Journal of biological chemistry High 17276987
2007 PKA phosphorylates BIG2 in vitro, decreasing its GEP activity; this phosphorylation is reversed by protein phosphatase 1gamma (PP1gamma) but not PP1alpha or PP1beta. Endogenous PP1gamma (not PP1alpha or PP1beta) co-immunoprecipitates with BIG2 from microsomal fractions, establishing PP1gamma as a regulator of BIG2 activity. In vitro PKA phosphorylation assay, siRNA depletion of BIG2, immunoprecipitation GEP activity assay, recombinant phosphatase treatment, Co-IP of PP1 isoforms Proceedings of the National Academy of Sciences of the United States of America High 17360629
2006 AMY-1 (associate of Myc-1) co-immunoprecipitates with both BIG2 and BIG1 in vitro, but localizes to the TGN specifically through interaction with BIG2 (not BIG1) as demonstrated by RNAi: depletion of BIG2 (not BIG1) disperses AMY-1 from the TGN. Co-immunoprecipitation using FLAG-tagged AMY-1, siRNA knockdown of BIG1 or BIG2, immunofluorescence localization of AMY-1 Genes to cells : devoted to molecular & cellular mechanisms Medium 16866877
2007 BIG2 (and BIG1) form homodimers through interactions between their conserved DCB domains; within each homodimer, the DCB domain also interacts with the HUS domain. The HUS box is the most conserved motif in large ArfGEFs after the Sec7 domain and mediates the DCB/HUS interaction. Yeast two-hybrid assays, biochemical interaction assays, deletion mutant analysis, cellular dimerization assays in mammalian cells The Journal of biological chemistry Medium 17640864
2008 Simultaneous knockdown of both BIG2 and BIG1 causes mislocalization of TGN/recycling endosome-associated proteins and blocks retrograde transport of furin from late endosomes to the TGN, a phenotype similar to depletion of AP-1, establishing BIG2 and BIG1 as redundant regulators of AP-1-dependent trafficking between TGN and endosomes. RNAi double knockdown, immunofluorescence localization of furin and TGN markers, comparison to AP-1 depletion Molecular biology of the cell Medium 18417613
2008 cAMP-induced release of TNFR1 exosome-like vesicles requires PKA activity and is mediated through BIG2's AKAP function: PKA regulatory subunit RIIbeta binds specifically to BIG2 AKAP domains B and C, and this interaction is required for both constitutive and cAMP-induced TNFR1 exosome-like vesicle release. siRNA knockdown of PKA regulatory subunits (RIIbeta), TNFR1 release assay, domain mapping of BIG2 AKAP sequences, 8-bromo-cAMP stimulation The Journal of biological chemistry Medium 18625701
2009 Phosphodiesterase 3A (PDE3A) physically associates with BIG2 (and BIG1) complexes; specific depletion of PDE3A by siRNA or its inhibition by cilostamide significantly decreases membrane-associated BIG2 and BIG1 and reduces activated ARF1-GTP, linking PDE3A-dependent cAMP regulation within BIG2 AKAP complexes to ARF1 activation. siRNA depletion of PDE3A, PDE3A-specific inhibitor cilostamide, confocal immunofluorescence, ARF1-GTP measurement Proceedings of the National Academy of Sciences of the United States of America Medium 19332778
2010 Depletion of BIG2 (but not BIG1) by siRNA induces tubulation of the recycling endosomal compartment, while BIG1 depletion causes Golgi fragmentation into mini-stacks; this demonstrates non-redundant and distinct functions for BIG2 (recycling endosome integrity) vs. BIG1 (Golgi morphology). siRNA knockdown, fixed and live-cell fluorescence imaging of Golgi and endosomal markers PloS one Medium 20360857
2012 The small G protein Arl1 is necessary and sufficient for Golgi recruitment of BIG2 (and BIG1) but not GBF1. Arl1 binds directly to the N-terminal region of Sec71 (the Drosophila ortholog of BIG1/BIG2), establishing Arl1 as the upstream recruiter that directs BIG2 specifically to the trans-Golgi. Liposome-based affinity purification to identify Arl1 effectors, Arl1 knockdown in mammalian cells, immunofluorescence of BIG1/BIG2/GBF1 Golgi localization The Journal of cell biology High 22291037
2012 BIG2 siRNA depletion causes perinuclear accumulation of integrin beta1 and delayed return to the cell surface, decreased cell motility, and reduced actin-based membrane protrusions; cytosolic levels of Arp2, Arp3, cofilin-1, phosphocofilin, vinculin, and Grb2 are increased, establishing BIG2 as a regulator of integrin beta1 recycling and actin dynamics in cell migration. siRNA knockdown, difference gel electrophoresis (DIGE) proteomics, immunofluorescence, wound-healing migration assay, integrin beta1 trafficking assay Proceedings of the National Academy of Sciences of the United States of America Medium 22908276
2013 GBF1-activated ARFs (ARF4 and ARF5, but not ARF3) facilitate BIG2 and BIG1 recruitment to the TGN, establishing a functional GEF cascade: GBF1 (pre-Golgi/Golgi/TGN) → ARF4/ARF5 activation → BIG1/BIG2 TGN recruitment → ARF activation for AP-1/GGA clathrin adaptor recruitment. GBF1 dominant-negative expression, ARF isoform-specific depletion, immunofluorescence of BIG1/BIG2 TGN localization, ultrastructural localization by immuno-EM The Journal of biological chemistry Medium 23386609
2013 BIG2 physically associates (reciprocal Co-IP) with nonmuscle myosin IIA in HeLa cells independently of its ARF-GEF activity; depletion of BIG2 (or BIG1) enhances phosphorylation of myosin regulatory light chain (T18/S19) and increases F-actin content, impairing cell migration. BIG2 anchors a myosin phosphatase complex containing myosin IIA, protein phosphatase 1delta, and myosin phosphatase-targeting subunit 1 (MYPT1). Reciprocal Co-IP of endogenous proteins, siRNA depletion, phospho-myosin light chain measurement, F-actin quantification, Transwell cell migration assay, rescue by BIG2 C-terminal overexpression Proceedings of the National Academy of Sciences of the United States of America High 23918382
2016 BIG2 (and BIG1) physically interact with beta-catenin; depletion of BIG1/BIG2 or expression of GEF-inactive mutants causes perinuclear Golgi accumulation of beta-catenin and reduces PKA-phosphorylated beta-catenin (S675). BIG2 AKAP-C sequence is required for PKA-dependent S675 phosphorylation and beta-catenin transcription coactivator function, requiring both ARF-GEF activity and phospholipase D-dependent vesicular trafficking. Co-IP (BIG1/BIG2 antibodies), yeast two-hybrid, in vitro protein synthesis, siRNA depletion, GEF-inactive mutant expression, phospho-beta-catenin Western blot, transcription reporter assay Proceedings of the National Academy of Sciences of the United States of America Medium 27162341
2018 BIG2 co-localizes with the Golgi apparatus in hippocampal neurons and is required for Golgi deployment into major dendrites. BIG2 acts through ARF1 to activate RhoA and its downstream effector mDia1, forming a BIG2-ARF1-RhoA-mDia1 signaling axis that regulates dendritic Golgi polarization and dendrite growth/maintenance. In vivo, ARFGEF2 shRNA delivered by in utero electroporation impairs Golgi deployment into the apical dendrite. shRNA knockdown, constitutively active ARF1 Q71L rescue, RhoA activation assay, LPA treatment rescue, immunofluorescence, in utero electroporation in mouse embryos Molecular neurobiology Medium 29455446
2019 BIG2 (and BIG1) knockdown significantly decreases VEGF mRNA and protein levels in glioblastoma U251 cells and HUVECs, and inhibits HUVEC angiogenesis by diminishing cell migration. Knockdown of the BIG2 homolog arfgef2 in zebrafish impairs angioblast migration and intersegmental vessel sprouting, and CRISPR/Cas9 deletion of arfgef2 causes vascular development defects, establishing a role for BIG2 in VEGF expression and angiogenesis beyond vesicular trafficking. siRNA knockdown, VEGF mRNA/protein quantification, HUVEC migration and angiogenesis assays, zebrafish morpholino knockdown and CRISPR/Cas9 deletion with vascular GFP imaging FASEB journal Medium 31199673
2025 In Drosophila neuroblasts, Arf1 and its GEF ARFGEF2/Sec71 control asymmetric division by facilitating cortical localization of nonmuscle myosin II regulatory light chain (Sqh). Arf1 physically associates with Sqh and with Vibrator (a type I PITP), and Arf1/Sec71 facilitate PI(4)P localization to the neuroblast cortex, linking PI(4)P production to myosin II cortical anchoring during asymmetric division. Genetic epistasis in Drosophila, Co-immunoprecipitation of Arf1 with Sqh and Vibrator, immunofluorescence of PI(4)P and myosin II cortical localization, loss-of-function neuroblast division assays Proceedings of the National Academy of Sciences of the United States of America Medium 40208939

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nature genetics 290 14647276
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
2008 BIG-2 mediates olfactory axon convergence to target glomeruli. Neuron 131 18367085
2004 BIG2, a guanine nucleotide exchange factor for ADP-ribosylation factors: its localization to recycling endosomes and implication in the endosome integrity. Molecular biology of the cell 121 15385626
2002 Overexpression of an ADP-ribosylation factor-guanine nucleotide exchange factor, BIG2, uncouples brefeldin A-induced adaptor protein-1 coat dissociation and membrane tubulation. The Journal of biological chemistry 93 11777925
2003 Protein kinase A-anchoring (AKAP) domains in brefeldin A-inhibited guanine nucleotide-exchange protein 2 (BIG2). Proceedings of the National Academy of Sciences of the United States of America 81 12571360
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
2002 Dominant-negative mutant of BIG2, an ARF-guanine nucleotide exchange factor, specifically affects membrane trafficking from the trans-Golgi network through inhibiting membrane association of AP-1 and GGA coat proteins. Biochemical and biophysical research communications 68 12051703
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
2007 The brefeldin A-inhibited guanine nucleotide-exchange protein, BIG2, regulates the constitutive release of TNFR1 exosome-like vesicles. The Journal of biological chemistry 56 17276987
2006 Association of brefeldin A-inhibited guanine nucleotide-exchange protein 2 (BIG2) with recycling endosomes during transferrin uptake. Proceedings of the National Academy of Sciences of the United States of America 53 16477018
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
2005 Interaction of BIG2, a brefeldin A-inhibited guanine nucleotide-exchange protein, with exocyst protein Exo70. Proceedings of the National Academy of Sciences of the United States of America 45 15705715
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
2010 Specific functions of BIG1 and BIG2 in endomembrane organization. PloS one 37 20360857
2006 Overlapping expression of ARFGEF2 and Filamin A in the neuroependymal lining of the lateral ventricles: insights into the cause of periventricular heterotopia. The Journal of comparative neurology 37 16320251
2009 Movement disorder and neuronal migration disorder due to ARFGEF2 mutation. Neurogenetics 32 19384555
2008 cAMP-dependent protein kinase A (PKA) signaling induces TNFR1 exosome-like vesicle release via anchoring of PKA regulatory subunit RIIbeta to BIG2. The Journal of biological chemistry 27 18625701
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
2006 AMY-1 (associate of Myc-1) localization to the trans-Golgi network through interacting with BIG2, a guanine-nucleotide exchange factor for ADP-ribosylation factors. Genes to cells : devoted to molecular & cellular mechanisms 25 16866877
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
2018 BIG2-ARF1-RhoA-mDia1 Signaling Regulates Dendritic Golgi Polarization in Hippocampal Neurons. Molecular neurobiology 23 29455446
2013 West syndrome, microcephaly, grey matter heterotopia and hypoplasia of corpus callosum due to a novel ARFGEF2 mutation. Journal of medical genetics 23 23812912
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
2005 Expression of BIG2 and analysis of its function in mammalian cells. Methods in enzymology 20 16413271
2003 Cloning and characterization of the human neural cell adhesion molecule, CNTN4 (alias BIG-2). Cytogenetic and genome research 20 14571131
2015 The expanding phenotypic spectrum of ARFGEF2 gene mutation: Cardiomyopathy and movement disorder. Brain & development 19 26126837
2014 Periventricular nodular heterotopia and dystonia due to an ARFGEF2 mutation. Pediatric neurology 19 25160555
2010 Early embryonic lethality in gene trap mice with disruption of the Arfgef2 gene. The International journal of developmental biology 18 20857375
2014 Filamin A mediated Big2 dependent endocytosis: From apical abscission to periventricular heterotopia. Tissue barriers 17 25097827
2012 Brefeldin A-inhibited ADP-ribosylation factor activator BIG2 regulates cell migration via integrin β1 cycling and actin remodeling. Proceedings of the National Academy of Sciences of the United States of America 14 22908276
2005 BIG1 and BIG2, brefeldin A-inhibited guanine nucleotide-exchange factors for ADP-ribosylation factors. Methods in enzymology 14 16413268
2013 Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: case study and literature review. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 12 23755938
1997 A novel splice variant of the cell adhesion molecule BIG-2 is expressed in the olfactory and vomeronasal neuroepithelia. Brain research. Molecular brain research 11 9221934
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
2014 Filamin A and Big2: a shared endocytic pathway. Bioarchitecture 9 24709996
2011 Nanomechanics of Ig-like domains of human contactin (BIG-2). Journal of molecular modeling 6 21445711
2025 Arf1 and ARFGEF2/Sec71 control neuroblast polarity by anchoring nonmuscle myosin II. Proceedings of the National Academy of Sciences of the United States of America 1 40208939
2026 A novel homozygous ARFGEF2 splice-site variant causing periventricular nodular heterotopia with microcephaly. Frontiers in pediatrics 0 42255913

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