Affinage

Showing CYTH2 — CYTOHESIN-2 is a alias.

CYTH2

Cytohesin-2 · UniProt Q99418

Length
400 aa
Mass
46.5 kDa
Annotated
2026-06-09
76 papers in source corpus 56 papers cited in narrative 56 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CYTH2 (cytohesin-2/ARNO) is a multidomain guanine nucleotide exchange factor that activates ARF GTPases at the plasma membrane and endosomes to couple receptor and lipid signals to membrane remodeling, cytoskeletal dynamics, and vesicular trafficking (PMID:9417041, PMID:11481345). Its catalytic Sec7 domain inserts a 'glutamic finger' (Glu156) that destabilizes Mg²⁺ and GDP to drive nucleotide exchange on ARF1 and ARF6, with the conserved hydrophobic groove engaging the ARF switch regions (PMID:9510256, PMID:9476900, PMID:9649435, PMID:14739276). Membrane recruitment is governed by its PH domain, which binds PIP3 in preference to PIP2 to deliver the enzyme to membranes upon PI3K-dependent stimulation (e.g. insulin), while a C-terminal polybasic region adds non-specific ionic contacts; PKC phosphorylation of Ser392 acts as an electrostatic switch that releases the enzyme from the membrane and downregulates exchange (PMID:9550703, PMID:10531036, PMID:10801341). On membranes the enzyme behaves as a positive-feedback bistable switch, being itself allosterically activated by ARF-GTP through its PH domain (PMID:21118813). Through ARF6, CYTH2 drives epithelial cell migration and lamellipodium formation via two parallel outputs—Rac1 activation through the Dock180/Elmo complex and phospholipase D activation (PMID:11481345, PMID:16213822), and contributes to neurite/axon outgrowth, Schwann cell myelination, podosome assembly, integrin recycling, insulin and granule secretion, and exocytosis (PMID:14565977, PMID:25824033, PMID:28007915, PMID:26378252, PMID:21276423, PMID:24581425, PMID:37091866). Localization, specificity, and signaling context are set by an N-terminal coiled-coil that scaffolds CASP, IPCEF1, GRASP, Gαq, and FE65 and by PH/polybasic interactions with ARL4D, paxillin, RLIP76, and aldolase (PMID:12052827, PMID:12920129, PMID:20016009, PMID:17846866, PMID:36168805, PMID:17804820, PMID:20525696, PMID:25450693, PMID:21307348). V-ATPase couples endosomal acidification to ARF activation: the a-subunit N-terminus binds the Sec7 domain in competition with ARF switch 2 and modulates GEF activity in a pH-dependent manner (PMID:11278939, PMID:16415858, PMID:23288846). CYTH2 also relays GPCR and receptor signaling, binding the A2A adenosine receptor, EGFR juxtamembrane segment, and MYD88 to sustain ERK signaling and to control endothelial barrier integrity (PMID:16027149, PMID:31780432, PMID:23143332). Beyond ARF activation, CYTH2 maintains Golgi volume and global protein secretion in an ARF-GEF-independent manner, and its full knockout is perinatally lethal in mice (PMID:41672711).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1997 High

    Established that CYTH2 is a bona fide ARF GEF and that its catalytic and membrane-targeting functions are separable—the Sec7 domain drives exchange while the PH domain binds PIP2 only for recruitment.

    Evidence In vitro nucleotide exchange assays on truncated and full-length myristoylated ARF1 with liposomes

    PMID:9268368

    Open questions at the time
    • Did not resolve atomic catalytic mechanism
    • ARF6 specificity untested in this system
  2. 1998 High

    Defined the structural basis of ARF recognition and the catalytic chemistry, identifying the Sec7 hydrophobic groove as the ARF-binding surface and Glu156 as the 'glutamic finger' that expels Mg²⁺ and GDP.

    Evidence Crystal structures at 2.0/2.2 Å with footprinting, plus site-directed mutagenesis (E156D/E156K) and stable complex isolation

    PMID:9476900 PMID:9510256 PMID:9649435

    Open questions at the time
    • Static structures did not capture the exchange transition state
    • Membrane context absent from crystallography
  3. 1998 High

    Placed CYTH2 at the plasma membrane acting on ARF6 in cells while remaining dual-specific in vitro, and linked it to PI3K-dependent, PIP3-driven translocation and PKC-induced actin remodeling.

    Evidence Subcellular fractionation, GFP-ARNO live imaging in adipocytes with PI3K inhibitors and dominant-negative p85, PKC phosphorylation and immunofluorescence

    PMID:9417041 PMID:9550703 PMID:9802902

    Open questions at the time
    • In vivo ARF6 vs ARF1 selectivity not quantified
    • Direct PKC site not yet mapped
  4. 1999 High

    Identified Ser392 as the PKC phosphorylation site and defined the PH-domain electrostatic switch by which phosphorylation displaces the enzyme from the membrane and inhibits exchange.

    Evidence In vitro phosphorylation, membrane binding and exchange assays with S392A mutant, in vivo translocation

    PMID:10531036

    Open questions at the time
    • Upstream PKC isoform not defined
    • Physiological trigger for dephosphorylation unresolved
  5. 2000 Medium

    Refined the lipid code—PH domain confers PIP3>PIP2 specificity while the polybasic C-terminus adds non-specific anionic binding—and connected CYTH2 catalysis to GPCR desensitization independent of PI3K.

    Evidence Lipid vesicle cosedimentation, in vitro exchange on vesicles, cell-free LH/CGR desensitization assay with E156K and PH mutants

    PMID:10801341 PMID:10811902

    Open questions at the time
    • Mechanistic link between ARF activation and beta-arrestin release incompletely defined
  6. 2001 High

    Defined the migration output of CYTH2 as ARF6-dependent and bifurcating into parallel Rac1 and PLD pathways, and showed V-ATPase-driven acidification recruits CYTH2/ARF6 to apical endosomes.

    Evidence ARF6-GTP and Rac pulldowns, PLD inhibitors, migration assays in MDCK; pH-dependent translocation assays with V-ATPase inhibitors; in vitro Sec7/ARF core domain-swap exchange assays

    PMID:11278939 PMID:11342560 PMID:11481345

    Open questions at the time
    • Identity of the Rac-GEF executing ARF6→Rac not yet known
    • Molecular nature of the V-ATPase contact unresolved
  7. 2002 Medium

    Began assigning scaffolding functions to the N-terminal coiled-coil, showing it recruits CASP to membrane ruffles.

    Evidence Yeast two-hybrid, pull-down, co-IP and immunofluorescence in EGF-stimulated cells

    PMID:12052827

    Open questions at the time
    • Functional consequence of CASP recruitment for ARF signaling not established
  8. 2003 Medium

    Identified coiled-coil partner IPCEF1 as a positive regulator of exchange and co-translocation, and showed CYTH2 mediates insulin-driven ARF/PLD activation with domain-specific contributions.

    Evidence Yeast two-hybrid, pull-down, co-IP, ARF-GTP assays; domain-deletion ARNO in insulin-stimulated cells; NMR/epistasis defining axonal roles

    PMID:12920129 PMID:12969509 PMID:14565977 PMID:14739276

    Open questions at the time
    • How IPCEF1 enhances catalysis mechanistically not resolved
    • Neuronal substrate of ARF6 incompletely defined
  9. 2005 High

    Connected CYTH2 to receptor-proximal sustained ERK signaling and identified the Dock180/Elmo complex as the executor of ARF6→Rac1 during migration.

    Evidence Yeast two-hybrid/co-IP for A2A receptor binding with inducible dominant-negatives; epistasis with catalytically dead Dock180 and Elmo mutants in MDCK

    PMID:16027149 PMID:16213822

    Open questions at the time
    • How ARF6-GTP recruits Dock180/Elmo mechanistically not shown
  10. 2006 High

    Defined the V-ATPase a2-subunit as a direct Sec7-domain interactor coupling endosomal acidification to ARF activation and trafficking, and established apical-specific localization governed by the coiled-coil.

    Evidence Co-IP, dominant-negatives, bafilomycin/concanamycin inhibition, endocytosis assays; GFP-ARNO localization and pIgR endocytosis with deletion mutants

    PMID:16415858 PMID:16484220

    Open questions at the time
    • Structural detail of the a2N–Sec7 contact not yet resolved
  11. 2007 Medium

    Mapped Gαq and ARL4D as upstream activators/recruiters of CYTH2 acting through the coiled-coil and PH/polybasic domains respectively, expanding the inputs that gate ARF6 output.

    Evidence Co-IP with purified proteins, coiled-coil deletion mutants, ARF6 activation, GFP-ARNO translocation with siRNA and E156K controls

    PMID:16650966 PMID:17623778 PMID:17804820 PMID:17846866

    Open questions at the time
    • Competition/hierarchy among multiple recruiters in a single cell unresolved
  12. 2010 High

    Established that CYTH2 is allosterically activated on membranes by ARF-GTP, defining a positive-feedback bistable switch, and identified scaffolds (GRASP/IPCEF1) and adaptors (paxillin) coordinating ARF-to-Rac signaling and migration.

    Evidence Kinetic liposome exchange assays with PH-domain mutants and effector competition; siRNA epistasis of GRASP/IPCEF1; paxillin domain-mapped co-IP and migration assays

    PMID:20016009 PMID:20525696 PMID:21118813

    Open questions at the time
    • In vivo evidence for the bistable switch lacking
    • Spatiotemporal triggering of feedback in cells not defined
  13. 2011 Medium

    Extended high-affinity PH-domain partnerships to aldolase and placed CYTH2 in a sequential Arf6→Cdc42→Rac1 cascade driving glucose-stimulated insulin secretion.

    Evidence SPR binding with recombinant proteins and siRNA; siRNA/dominant-negative/SecinH3 with sequential GTPase pulldowns in beta-cells and islets

    PMID:21276423 PMID:21307348

    Open questions at the time
    • Physiological role of aldolase binding unclear
    • Direct effectors linking Arf6 to Cdc42 not identified
  14. 2012 High

    Demonstrated CYTH2 as an inflammatory effector via a direct MYD88–ARNO–ARF6 complex controlling endothelial barrier integrity, validating pharmacological inhibition (SecinH3) in vivo; and identified it as a host factor for Salmonella invasion.

    Evidence Co-IP/direct binding, dominant-negatives, permeability assays, in vivo arthritis model; RNAi screen and invasion assays with WRC recruitment

    PMID:22341462 PMID:23143332

    Open questions at the time
    • How MYD88 binding activates ARF6 mechanistically not detailed
  15. 2013 High

    Resolved the structural mechanism of V-ATPase a-subunit inhibition of GEF activity (a2N competing with ARF switch 2) and demonstrated druggable pockets on the Sec7 surface.

    Evidence In vitro GEF assays, NMR structure of a2N(1-17), docking, conservation across a-subunit isoforms; fragment-based design with X-ray Sec7–fragment complexes

    PMID:23288846 PMID:24112024

    Open questions at the time
    • Cellular conditions selecting V-ATPase inhibition vs activation not defined
  16. 2014 Medium

    Established physiological roles in platelet granule secretion (constitutive ARF6 suppression relieved by PKC), neurite vesicle transport via CCDC120, preadipocyte migration, and identified the RLIP76 N-terminus as a CYTH2 partner.

    Evidence Phospho-IP/MS and aggregometry in platelets; CCDC120 co-IP/siRNA rescue with live imaging; inhibitor panels with ARF6/ERK assays; RLIP76 domain-mapped co-IP with functional assays

    PMID:24581425 PMID:25326380 PMID:25450674 PMID:25450693

    Open questions at the time
    • PKC site in platelet context not pinpointed
    • RLIP76 phospho-regulation of CYTH2 binding incompletely defined
  17. 2015 High

    Demonstrated an in vivo requirement for CYTH2 in Schwann cell myelination (conditional knockout reduces ARF6 activity and myelin) and defined RLIP76-linked R-Ras/integrin recycling through recycling endosomes.

    Evidence Schwann cell conditional knockout with EM myelin measurement and ARF6 assays; RLIP76 domain mutants, EHD1/Rab11 localization, GEF-dead E156K, integrin recycling assays

    PMID:25824033 PMID:26378252 PMID:26498519

    Open questions at the time
    • Downstream ARF6 effectors in myelination not identified
  18. 2016 High

    Showed CYTH2 acting through ARF1 (not solely ARF6) is required for podosome assembly by suppressing a RhoA/myosin-IIA axis.

    Evidence siRNA, pharmacological inhibition, ARF1-GTP pulldown, constitutively active ARF1, myosin-IIA inhibition rescue in multiple cell types

    PMID:28007915

    Open questions at the time
    • Link between ARF1-GTP and RhoA suppression mechanistically open
  19. 2019 Medium

    Structurally characterized direct CYTH2 binding to the EGFR juxtamembrane segment, embedding it in a regulated receptor-proximal modulatory network.

    Evidence NMR of the ARNO–EGFR JM interface and direct binding assays

    PMID:31780432

    Open questions at the time
    • No full cellular functional validation of the EGFR interaction
  20. 2018 High

    Uncovered a GEF-activity-independent function: the IBD risk protein INAVA stably binds CYTH2 to drive junctional F-actin and to restrain TRAF6-dependent inflammatory ubiquitination.

    Evidence Co-IP/domain binding, F-actin assays, GEF-dead ARNO, TRAF6 ubiquitination assays in epithelial cells and macrophages

    PMID:30355448

    Open questions at the time
    • Mechanism by which ARNO binding modulates CUPID/TRAF6 not fully resolved
  21. 2021 High

    Extended CYTH2 to neuronal physiology and viral infection: it complexes with mGluR5 to drive spinal pain signaling, stabilizes CNKSR2 against degradation in hippocampal neurons, and is required for influenza endosomal trafficking.

    Evidence Conditional knockout mice with behavioral/Arf6/ERK assays; co-IP with shRNA and proteasome rescue; genome-wide CRISPR screen with knockout and SecinH3 in vivo

    PMID:34390832 PMID:34800437 PMID:35354039

    Open questions at the time
    • How CYTH2 binding prevents CNKSR2 degradation mechanistically open
  22. 2022 High

    Defined Tyr381 phosphorylation (SH2B1 writer / PTP4A1 eraser) as a myelination control switch, linked the CYTH2/ARF1 axis to JNK–IRE1–XBP1 signaling in osteoclasts, and showed FE65 potentiates ARF6-driven neurite outgrowth by relieving ARNO autoinhibition.

    Evidence Y381F knockin and conditional knockdowns with phospho-antibody and ARF6 assays; siRNA/SecinH3 with RNA-seq and pathway assays in OVX osteoporosis model; FE65 co-IP and neurite outgrowth with dimerization mutants

    PMID:35077201 PMID:36168805 PMID:36252772

    Open questions at the time
    • How Tyr381 phosphorylation alters GEF behavior structurally not defined
  23. 2023 Medium

    Placed the V-ATPase V0a1 subunit as an upstream activator of the ARNO–Arf6–PLD1 pathway during regulated exocytosis in neuroendocrine cells.

    Evidence Co-IP, interaction disruption, PLD/phosphatidic acid/exocytosis-timing and Arf6 assays

    PMID:37091866

    Open questions at the time
    • Direct activation mechanism by V0a1 versus a2N inhibition not reconciled
  24. 2026 High

    Established that CYTH2 is essential for organismal viability and maintains Golgi volume and global protein secretion through an ARF-GEF-independent activity, separating its catalytic and structural roles.

    Evidence Full knockout mouse (perinatal lethality), organellar/quantitative proteomics, peanut agglutinin staining, ARF-GEF-independent re-expression rescue

    PMID:41672711

    Open questions at the time
    • Molecular basis of the ARF-GEF-independent Golgi function unknown
    • Cause of perinatal lethality not pinpointed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CYTH2 integrates its many competing recruiters and post-translational switches to select a specific ARF (ARF1 vs ARF6) and a specific downstream output in a given cellular context remains unresolved, as does the molecular basis of its ARF-GEF-independent Golgi/secretory function.
  • No unified model for context-dependent ARF1/ARF6 selectivity
  • ARF-GEF-independent mechanism uncharacterized
  • Structural picture of full-length autoinhibited vs activated enzyme on membranes incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0060090 molecular adaptor activity 4 GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 3 GO:0005829 cytosol 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9609507 Protein localization 3 R-HSA-168256 Immune System 2
Partners
ARF1ARF6ARL4DGNAQINAVAIPCEF1MYD88RALBP1
Complex memberships
ARNO–ARF6–FE65 complexARNO–Dock180/Elmo Rac signaling complexMYD88–ARNO–ARF6 complex

Evidence

Reading pass · 56 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 ARNO activates ARF1 through its Sec7 domain catalytic activity; the PH domain binds PIP2 to recruit ARNO to membranes, but PIP2-PH interaction does not directly regulate catalytic activity — it serves only for membrane recruitment. Efficient activation of full-length ARF1 requires two distinct protein-phospholipid interactions: PH domain binding PIP2 and electrostatic interactions between ARF1 N-terminal cationic residues and anionic phospholipids. In vitro nucleotide exchange assay on soluble truncated ARF1 ([Δ17]ARF1) and full-length myristoylated ARF1 with liposomes; isolation of stable Sec7-nucleotide-free ARF1 complex The Journal of biological chemistry High 9268368
1998 Crystal structure of the Sec7 domain of ARNO resolved at 2.0 Å; the domain is an elongated all-helical protein with a conserved hydrophobic groove and adjacent loop identified as the ARF-interacting surface. Structure-based mutagenesis confirmed the groove and loop as the ARF1-binding site. X-ray crystallography at 2.0 Å; structure-based mutagenesis Nature High 9510256
1998 Crystal structure of the Sec7 domain of ARNO determined at 2.2 Å; protein footprinting mapped ARF1 interaction sites to the switch 1 and switch 2 GTPase regions, providing a model for ARF GTPase–Sec7 domain exchange factor interaction. X-ray crystallography at 2.2 Å; protein footprinting experiments Cell High 9476900
1998 Glu156 in the hydrophilic loop of the ARNO Sec7 domain acts as a 'glutamic finger' that destabilizes Mg2+ and GDP from ARF1. Conservative mutation E156D and charge-reversal E156K each reduce exchange activity by several orders of magnitude. E156K forms a complex with Mg2+-free ARF1-GDP without inducing GDP release. Lys73 of ARF1 switch II forms an ion pair with Asp183 of ARNO-Sec7. Site-directed mutagenesis; in vitro nucleotide exchange assays; stable complex isolation The EMBO journal High 9649435
1998 ARNO localizes to the plasma membrane in mammalian cells (not the Golgi) and stimulates nucleotide exchange on both ARF1 and ARF6 in vitro, indicating its likely in vivo function is at the plasma membrane through ARF6 modulation. Subcellular fractionation; immunolocalization; in vitro nucleotide exchange assay The Journal of biological chemistry High 9417041
1998 ARNO PH domain binds PIP3 with higher affinity than PI(4,5)P2; insulin stimulation of 3T3-L1 adipocytes causes rapid PI3K-dependent, PH-domain-dependent translocation of GFP-ARNO to the plasma membrane. Translocation is blocked by wortmannin, LY294002, and dominant-negative p85. GFP-ARNO live imaging in adipocytes; PI3K inhibitors; dominant-negative p85 co-expression; in vitro PIP3 binding assay Current biology : CB High 9550703
1998 ARNO overexpression in vivo inhibits the early secretory pathway and causes Golgi disassembly; newly synthesized cargo fails to acquire endoglycosidase H resistance, indicating a block in ER-to-Golgi or early Golgi transport. ARNO overexpression does not affect early endocytosis. Immunofluorescence; cell fractionation; SEAP secretion assay; endoglycosidase H sensitivity assay Journal of cell science Medium 9788883
1998 PKC phosphorylates ARNO in vivo; co-treatment of ARNO-expressing HeLa cells with PKC agonist PMA induces redistribution of ARNO, ARF6, and actin into lamellipodia-like membrane protrusions. This actin rearrangement requires ARNO catalytic activity and the PH domain (membrane localization). Deletion of the PH domain abolishes cytoskeletal reorganization. PKC phosphorylation assay; overexpression of WT and catalytically inactive ARNO mutants; immunofluorescence Molecular biology of the cell Medium 9802902
1999 PKC phosphorylates ARNO at S392 within its C-terminal polybasic domain, negatively regulating exchange activity through a 'PH domain electrostatic switch': introducing a negative charge reduces ARNO membrane interaction both in vitro and in vivo, and inhibits exchange in vitro. This represents electrostatic regulation of PH-domain-dependent membrane binding. In vitro phosphorylation; membrane binding assays; in vitro nucleotide exchange assay; S392A mutagenesis Current biology : CB High 10531036
2000 ARNO PH domain provides specific PIP3 > PIP2 binding; the polybasic C-terminal extension contributes non-specific ionic interactions with acidic phospholipids. PKC phosphorylation of Ser in the C domain reduces ionic affinity for PS but does not affect phosphoinositide specificity. PIP3 is more stimulatory than PIP2 for ARNO-catalyzed ARF activation on vesicles. Cosedimentation of PH+C and nominal PH domain constructs with lipid vesicles; in vitro exchange assays on vesicles Biochemistry Medium 10801341
2000 ARNO promotes release of beta-arrestin from its membrane docking site in ovarian follicular membranes, enabling beta-arrestin binding to the LH/CGR third intracellular loop and receptor desensitization. This requires ARNO catalytic activity (E156K blocks desensitization) and PH domain-mediated membrane association. LH/CGR activation of ARNO is PI3K-independent and Gβγ-independent. Cell-free plasma membrane desensitization assay; Western blot for beta-arrestin; dominant-negative and PH-domain mutant ARNO Proceedings of the National Academy of Sciences of the United States of America Medium 10811902
2001 ARNO catalytic activity (GEF for ARF6, not ARF1) drives MDCK epithelial cell migration and lamellipodium formation. ARNO-induced motility requires downstream activation of Rac1 and phospholipase D (PLD), which operate as two distinct parallel pathways: PLD inhibition blocks motility without preventing Rac activation. Dominant-negative and active mutant expression; pulldown ARF6-GTP assay; Rac activation assay; PLD inhibitors; migration assay The Journal of cell biology High 11481345
2001 ARNO and ARF6 are recruited from cytosol to proximal tubule apical endosomes in a pH-dependent manner driven by V-ATPase-dependent acidification; translocation is reversed by V-ATPase inhibitors and pH uncouplers, and correlates with intra-endosomal acidification magnitude. Subcellular fractionation; translocation assay with ATP-driven acidification; Western blot; V-ATPase inhibitors The Journal of biological chemistry High 11278939
2001 In vitro, ARNO activates ARF1 preferentially and ARF6 only slightly; these selectivities are determined by the Sec7 domains alone and by the ARF core domains (not the N-terminal myristoylated helix), without depending on PH or N-terminal domains. In vitro exchange assay on membranes with isolated Sec7 domains and ARF core domains; chimeric ARF constructs The Journal of biological chemistry High 11342560
2002 The N-terminal coiled-coil domain of ARNO/cytohesin-2 interacts with the scaffolding protein CASP via CASP's internal coiled-coil motif. In EGF-stimulated cells, cytohesin recruits CASP to membrane ruffles, demonstrating a functional interaction. Yeast two-hybrid screening; in vitro pull-down; co-immunoprecipitation in COS-1 cells; immunofluorescence The Journal of biological chemistry Medium 12052827
2003 IPCEF1 binds the coiled-coil domain of cytohesin-2; cytohesin-2 binding domain maps to the C-terminal 121 aa of IPCEF1. Interaction confirmed in mammalian cells by co-IP. IPCEF1 increases both in vitro and in vivo ARF-GTP formation by cytohesin-2; IPCEF1 co-migrates with cytohesin-2 to the plasma membrane in EGF-stimulated cells only when the binding site is intact. Yeast two-hybrid; GST pull-down; co-immunoprecipitation; ARF-GTP formation assay; immunofluorescence The Journal of biological chemistry Medium 12920129
2003 ARNO mediates ARF activation and PLD activity downstream of insulin signaling; insulin-induced ARNO translocation to plasma membrane requires the PH domain, and the Sec7 domain is required for downstream ARF translocation and PLD activation. The coiled-coil domain contributes to partial membrane targeting. Transient transfection of WT and domain-deletion/Sec7-mutant ARNO in HIRcB cells; insulin stimulation; ARF translocation assay; PLD activity assay BMC cell biology Medium 12969509
2003 ARNO and ARF6 regulate axonal elongation and branching in hippocampal neurons; catalytically inactive ARNO or dominant-negative ARF6 enhance axonal extension and branching. PI(4)P 5-kinase alpha acts downstream of ARF6 to regulate neurite extension. Inactive ARNO/ARF6 depletes Mena from growth cone leading edges. Expression of dominant-negative and constitutively active constructs in cultured rat hippocampal neurons; immunofluorescence for Mena; epistasis by co-expression Molecular biology of the cell Medium 14565977
2004 NMR analysis of Arf1 complexed with ARNO-Sec7; Glu156 is required to promote GDP release (E156A and E156K mutants release Mg2+ from Arf1-GDP but do not promote GDP release); the wild-type Sec7 domain weakly competes with GDP on Arf1-GDP-Mg2+ and leads to GDP release; ARNO-Sec7 does not interact appreciably with GTP-bound Arf1. 31P NMR spectroscopy; Arf1-GDP/GTP-Mg2+ complex analysis; mutant ARNO-Sec7 interaction studies The Journal of biological chemistry Medium 14739276
2004 Cytohesin-2 is required for serum response element (SRE)-mediated transcriptional activation and MAPK signaling; an RNA aptamer specific for cytohesin-2 (discriminating it from cytohesin-1) binds the N-terminal coiled-coil/Sec7 interface and in vivo downregulates SRE-mediated gene expression and MAPK activation. Cytohesin-1 does not substitute for this function. RNA aptamer ('intramer') transfection; SRE-reporter assay; MAPK activation assay in HeLa cells Proceedings of the National Academy of Sciences of the United States of America Medium 15277685
2005 ARNO directly binds the C-terminus (juxtamembrane portion) of the A2A adenosine receptor; this interaction is required for the sustained (heterotrimeric G protein-independent) phase of ERK/MAP kinase activation. Dominant-negative ARNO (E156K) and dominant-negative ARF6 (T27N) abolish sustained MAP kinase stimulation but do not affect cAMP accumulation or receptor desensitization. Yeast two-hybrid; mutual pull-down of bacterial fusion proteins; co-immunoprecipitation in mammalian cells; inducible dominant-negative cell lines; cAMP and ERK assays The Journal of biological chemistry High 16027149
2005 ARNO-dependent Rac1 activation in migrating MDCK cells is mediated by the Dock180/Elmo bipartite Rac-GEF complex. Catalytically inactive Dock180 and an Elmo mutant that cannot couple to Dock180 both block ARNO-induced Rac activation and motility. Beta-PIX (another Rac-GEF) does not mediate this pathway. Dominant-negative Dock180 and Elmo mutant expression; co-localization; Rac activation assay; migration assay in MDCK cells Current biology : CB High 16213822
2006 ARNO interacts with the a2-isoform of V-ATPase on early endosomes in an intra-endosomal acidification-dependent manner; ARF6 interacts with the c-subunit. Disruption of the V-ATPase–ARNO interaction reversibly inhibits endocytosis. Inhibition of endosomal acidification blocks protein trafficking from early to late endosomes. Co-immunoprecipitation; subcellular fractionation; dominant-negative constructs; bafilomycin/concanamycin A inhibition; endocytosis assays Nature cell biology High 16415858
2006 In polarized epithelial cells, ARNO localizes exclusively to the apical plasma membrane and regulates apical endocytosis; ARF6 co-expression synergistically stimulates apical endocytosis. The N-terminal coiled-coil domain is required for apical specificity: deletion causes ARNO mislocalization to both membranes, and expression of the CC domain alone abolishes apical endocytosis. GFP-ARNO expression in MDCK cells; polymeric immunoglobulin receptor endocytosis assay; deletion mutants; immunofluorescence The Journal of biological chemistry Medium 16484220
2006 Activated Gαq forms molecular complexes with ARNO and ARF6, preferentially with GTP-bound Gαq. Gαq interacts directly with ARNO (binding experiments with purified proteins). Gαq-dependent ARF6 activation leads to PI(4,5)P2 production and TPβ receptor internalization, both blocked by dominant-negative ARNO and ARF6. Co-immunoprecipitation; purified protein binding assay; dominant-negative mutants; ARF6-GTP pulldown; PI(4,5)P2 assay; receptor internalization assay Cellular signalling Medium 16650966
2007 ARL4D recruits cytohesin-2/ARNO to the plasma membrane in a GTP- and N-terminal myristoylation-dependent manner through direct interaction with the ARNO PH and polybasic C domains. Active ARL4D increases GTP-ARF6 levels and induces actin stress fiber disassembly; this requires ARNO catalytic activity and ARNO expression (inactive ARNO E156K or ARNO siRNA blocks ARL4D-mediated actin effects). ARL4D-induced CYTH2 translocation is PI3K-independent. Co-immunoprecipitation; GFP-ARNO translocation assay; ARF6-GTP pulldown; siRNA knockdown; dominant-negative ARNO; immunofluorescence Molecular biology of the cell High 17804820
2007 The coiled-coil domain of the cytohesin/ARNO family interacts with Gαq; cytohesin-2/ARNO and cytohesin-1 mutants lacking the coiled-coil domain cannot relay Gαq-mediated ARF6 activation. Cytohesin-1 preferentially associates with constitutively active Gαq-Q209L. Co-immunoprecipitation; coiled-coil deletion mutants; ARF6 activation assay; immunofluorescence Molecular and cellular biochemistry Medium 17846866
2007 CaSR stimulation induces plasma membrane ruffling via a pathway involving beta-arrestin 1, ARNO, ARF6, and ELMO. Beta-arrestin 1 co-immunoprecipitates with CaSR and ARNO under resting conditions; agonist treatment causes translocation of CaSR, beta-arrestin 1, and ARNO to membrane protrusions. Catalytically inactive ARNO reduces ruffling. ARF6 and ELMO are required downstream. Co-immunoprecipitation; siRNA knockdown; dominant-negative ARNO; dominant-negative beta-arrestin 1; immunofluorescence Journal of cell science Medium 17623778
2009 ARNO-induced Rac activation and migration require the coiled-coil domain; the coiled-coil promotes assembly of a multiprotein complex containing ARNO and Dock180. Knockdown of either GRASP/Tamalin or IPCEF1 (which bind the ARNO coiled-coil) prevents ARNO–Dock180 association and ARNO-induced Rac activation, placing scaffold proteins as coordinators of ARF-to-Rac signaling. Co-immunoprecipitation; siRNA knockdown of GRASP and IPCEF1; coiled-coil deletion mutant; Rac activation assay; migration assay Molecular biology of the cell Medium 20016009
2010 Paxillin (focal adhesion adaptor) forms a complex with cytohesin-2 mediated by the LIM2 domain of paxillin and the polybasic region of cytohesin-2. Paxillin co-localizes with cytohesin-2 at leading edges of migrating 3T3-L1 cells. siRNA knockdown of cytohesin-2 inhibits migration and its effects are upstream of ARF6. Co-immunoprecipitation; domain mapping with deletion mutants; siRNA knockdown; migration assay; immunofluorescence The Journal of biological chemistry Medium 20525696
2010 On model membranes, Arf6-GTP activates Arno at nanomolar concentrations (vs. micromolar in solution); mutations in the PH domain abolishing Arf6-GTP interaction render Arno completely inactive on liposomes but not in solution. Arno is also activated by its own product Arf1-GTP (positive feedback), behaving as a bistable switch requiring an Arf activator; Arno activity is modulated by competition with Arf effectors. Kinetic nucleotide exchange assays on liposomes with membrane-anchored full-length Arf1 and Arf6; PH domain mutants; competition experiments with Arf effectors The Journal of biological chemistry High 21118813
2010 The N-terminus of the V-ATPase a2-subunit interacts with multiple domains of ARNO; the a2N-01 peptide (MGSLFRSESMCLAQLFL) specifically binds the Sec7 domain with KD ~3.44×10⁻⁷ M. In silico docking shows a2N competes with switch 2 of Arf1/Arf6 for Sec7 domain binding. Phosphorylation of ARNO Ser392 abolishes a2N binding to the ARNO PB domain. Synthetic peptide pull-down assays; surface plasmon resonance; NMR structure determination of peptides; homology modeling/in silico docking Biochimica et biophysica acta Medium 20153292
2011 ARNO directly interacts with aldolase via the ARNO PH domain; surface plasmon resonance yields KD = 2.84×10⁻¹⁰ M. Aldolase associates with early endosomal membranes. Aldolase knockdown in HeLa cells causes morphological changes and acidic vesicle redistribution, and is inversely correlated with gelsolin levels. Pull-down with recombinant proteins (GST-PH domain); surface plasmon resonance; subcellular fractionation; siRNA knockdown; immunofluorescence American journal of physiology. Cell physiology Medium 21307348
2011 ARNO promotes sequential activation of Arf6, then Cdc42, then Rac1 in pancreatic β-cells to stimulate glucose-stimulated insulin secretion (GSIS). siRNA-ARNO, dominant-negative ARNO (E156K), and SecinH3 each inhibit GSIS and block glucose-induced Arf6 activation in INS 832/13 cells and rat islets. ARNO–Arf6 complex association increases in glucose-stimulated β-cells. siRNA knockdown; dominant-negative mutant expression; SecinH3 inhibitor; GST-GGA3 ARF6-GTP pulldown; PAK-1 Rac/Cdc42 pulldown; co-immunoprecipitation; confocal microscopy Biochemical pharmacology Medium 21276423
2012 ARNO directly binds the adaptor protein MYD88, forming a MYD88–ARNO–ARF6 signaling complex. IL-1β activates ARF6 through this pathway in endothelial cells in an NF-κB-independent manner, disrupting endothelial barrier function. SecinH3 (ARNO inhibitor) enhances vascular stability and improves outcomes in animal models of inflammatory arthritis. Co-immunoprecipitation; direct binding assays; dominant-negative ARF6/ARNO; in vitro permeability assay; in vivo inflammatory arthritis model with SecinH3 Nature High 23143332
2012 During Salmonella invasion, ARNO is recruited via Arf6 and SopB-induced PIP3 generation; ARNO in turn triggers WAVE regulatory complex (WRC) recruitment and activation for membrane ruffling and macropinosome formation. RNAi screening identified ARNO as a key host Arf-GEF for Salmonella invasion. RNAi screen; siRNA knockdown; fluorescence microscopy; invasion assay; Arf6-GTP pulldown Cell host & microbe Medium 22341462
2013 The N-terminal cytosolic tail of V-ATPase a2-subunit (first 17 aa, a2N(1-17)) potently inhibits cytohesin-2 GEF activity by directly interacting with the Sec7 domain, competing with ARF switch 2. Structure of a2N(1-17) and key residues Phe5, Met10, Gln14 involved in Sec7 binding were determined by NMR. This signaling mechanism is conserved across all four mammalian V-ATPase a-subunit isoforms. In vitro GEF activity assay; NMR spectroscopy; in silico docking; pull-down with recombinant proteins; binding to intact yeast V-ATPase The Journal of biological chemistry High 23288846
2013 Fragment-based drug design identified small molecules that bind directly to specific pockets on the ARNO Sec7 domain surface and inhibit Arno-catalyzed nucleotide exchange on ARF1; binding modes of two compounds resolved by X-ray crystallography, revealing stable and transient pockets at the Sec7 surface. SPR; NMR; fluorescence assays; X-ray crystallography of Sec7–fragment complexes; in vitro exchange inhibition assay Journal of medicinal chemistry High 24112024
2014 Cytohesin-2 constitutively suppresses platelet dense granule secretion by maintaining ARF6 in a GTP-bound state; PKC-mediated phosphorylation of cytohesin-2 relieves this suppression. SecinH3 enhances dense granule secretion and aggregation but not α-granule release or αIIbβ3 activation. ARF6 interaction with cytohesin-2 decreases upon platelet stimulation in a PKC-dependent manner. Immunoprecipitation with phosphoserine-PKC antibody; mass spectrometry; lumi-aggregometry; flow cytometry; Western blotting; SecinH3 pharmacological inhibition Journal of thrombosis and haemostasis : JTH Medium 24581425
2014 Cytohesin-2 interacts with CCDC120 via the CC1 coiled-coil domain; CCDC120 localizes cytohesin-2 into vesicles that undergo anterograde transport along neurites. CCDC120 knockdown inhibits cytohesin-2 vesicular localization, Arf6 activation, and neurite growth; these are rescued by WT CCDC120 but not by CC1-domain-deficient CCDC120. Co-immunoprecipitation; siRNA knockdown; live vesicle transport imaging; Arf6-GTP assay; rescue experiments The Journal of biological chemistry Medium 25326380
2014 Cytohesin-2 activates ARF6 in a PI3K-dependent manner; active ARF6 causes ERK1/2 phosphorylation during preadipocyte migration. Dynamin inhibition blocks migration but not ARF6 or ERK1/2 activation. siRNA knockdown; pharmacological inhibitors (SecinH3, LY294002, PD98059, dynasore); ARF6-GTP pulldown; ERK phosphorylation by Western blot; migration assay Biochemical pharmacology Medium 25450674
2014 RLIP76 N-terminal domain (residues 1-180) binds ARNO; Ser29/30 in the N-terminus are required for ARNO interaction and for RLIP76-dependent cell spreading, migration, Arf6 activation, and PI3K activation. Ser62 supports ARNO binding and Arf6 activation but Ser62A still blocks Rac1 activation. Co-immunoprecipitation; domain deletion and point mutants; cell spreading/migration assay; ARF6-GTP pulldown; Rac1 activation assay; PI3K activation assay Biochemical and biophysical research communications Medium 25450693
2015 Cytohesin-2/ARNO regulates myelin sheath thickness in peripheral nerves; Schwann cell-specific conditional knockout of cytohesin-2 reduces Arf6 activity, myelin thickness, and MPZ expression in sciatic nerves without affecting cell proliferation. Schwann cell-specific conditional knockout mouse; myelin thickness measurement (electron microscopy); ARF6-GTP assay; Western blot for MPZ; Ki67 staining; SecinH3 treatment of Schwann cell-neuron co-cultures Biochemical and biophysical research communications High 25824033
2015 RLIP76 links ARNO to activated R-Ras at Rab11-positive recycling endosomes; RLIP76 binds ARNO via residues 1-180 and R-Ras via residues 180-192. ARNO localization to recycling endosomes requires RLIP76 and its ARNO-binding domain. Cytohesin-2/ARNO regulates recycling of R-Ras and α5-integrin to the plasma membrane via ARF activation. Co-immunoprecipitation; domain deletion mutants; immunofluorescence; ARF6-GTP assay; integrin recycling assay Biochemical and biophysical research communications Medium 26498519
2015 Cytohesin-2/ARNO regulates R-Ras and α5-integrin recycling through an EHD1-positive recycling endosome compartment; GEF-inactive ARNO (E156K) accumulates R-Ras on recycling endosomes and inhibits cell spreading; ARNO catalytic activity is required for focal adhesion formation and integrin recycling. Co-localization studies; GEF-inactive E156K-ARNO expression; integrin recycling assay; focal adhesion quantification; siRNA knockdown Molecular biology of the cell Medium 26378252
2016 ARNO (co-localizing with podosome adhesive rings) and ARF1 are required for podosome assembly; ARNO/ARF1 knockdown or pharmacological inhibition eliminates podosomes and elevates RhoA-GTP and myosin-IIA filaments. Constitutively active ARF1 induces podosome precursor structures. Suppression of myosin-IIA rescues podosome formation despite ARF1 inhibition, placing RhoA/myosin-II downstream of ARNO/ARF1. siRNA knockdown; pharmacological inhibitors; ARF1-GTP pulldown; immunofluorescence; constitutively active ARF1 expression; myosin-IIA inhibition rescue The Journal of cell biology High 28007915
2018 INAVA (IBD risk gene) CUPID domain stably binds ARNO and effects F-actin assembly at lateral membranes underlying cell-cell junctions in an ARNO-dependent but GEF-activity-independent manner. Upon IL-1β stimulation, INAVA relocates to cytosolic puncta where CUPID amplifies TRAF6-dependent polyubiquitination; ARNO binding to CUPID negatively-regulates this inflammatory polyubiquitination. INAVA and ARNO act similarly in human macrophages. Co-immunoprecipitation; domain binding assays; F-actin assembly assay; GEF-inactive ARNO; TRAF6 polyubiquitination assay; IL-1β stimulation in epithelial cells and macrophages eLife High 30355448
2019 ARNO directly binds the juxtamembrane (JM) segment of EGFR intracellular domain; the ARNO-EGFR interaction interface was structurally characterized by NMR and shows common features but distinct differences from JM interactions with calmodulin and anionic phospholipids, forming a regulated modulatory network. NMR spectroscopy; direct binding assays Structure (London, England : 1993) Medium 31780432
2021 CYTH2 (cytohesin-2) is required for the early stage of influenza virus infection by mediating endosomal trafficking; CYTH2 knockout reduces efficient infection, and the CYTH2 antagonist SecinH3 blunts influenza virus infection in vivo. Genome-wide CRISPR-Cas9 screen; CYTH2 knockout validation; SecinH3 in vivo treatment; infection efficiency assay Cell reports Medium 35354039
2021 CNKSR2 forms a molecular complex with CYTH2 in the hippocampus; CYTH2 binding prevents proteasomal degradation of CNKSR2. Knockdown of either CNKSR2 or CYTH2 in granule cell precursors in vivo results in abnormal localization of cells at the granule cell layer/hilus boundary with characteristics of immature granule cells. Co-immunoprecipitation; shRNA knockdown in vivo via viral transduction; immunofluorescence; proteasome inhibitor rescue The Journal of biological chemistry Medium 34800437
2021 Cytohesin-2 forms a protein complex with mGluR5 in the spinal cord and is enriched in the perisynapse of dorsal horn neurons. CNS-specific cytohesin-2 conditional knockout mice show reduced mechanical allodynia in inflammatory and neuropathic pain models. SecinH3 inhibits spinal Arf6 (not Arf1) activation. Cytohesin-2 knockout reduces ERK1/2 activation following spinal mGluR1/5 activation. Co-immunoprecipitation; conditional knockout mice; SecinH3 pharmacological inhibition; mechanical allodynia behavioral testing; Arf6/Arf1-GTP assay; ERK phosphorylation assay Neurobiology of disease High 34390832
2022 Phosphorylation of cytohesin-2 at Tyr381 is central to Schwann cell myelination; knockin mice with Y381F mutation show reduced myelin thickness and decreased Arf6 activity. PTP4A1 dephosphorylates cytohesin-2 at Tyr381; SH2B1 maintains phosphorylation. Schwann cell-specific knockdown of PTP4A1 increases cytohesin-2 phosphorylation and myelin thickness; loss of SH2B1 reduces both. Knockin mouse (Y381F); conditional Schwann cell knockdown of PTP4A1 and SH2B1; phospho-specific antibody; ARF6-GTP assay; myelin thickness measurement Science signaling High 35077201
2022 Cytohesin-2/ARF1 axis positively regulates osteoclast differentiation; blocking it with SecinH3 or cytohesin-2 siRNA inhibits osteoclast formation and function in vitro and ameliorates ovariectomy-induced osteoporosis in vivo. Mechanistically, cytohesin-2/ARF1 activates the JNK pathway; JNK in turn regulates IRE1 endoribonuclease activity (not kinase) to promote XBP1 splicing. siRNA knockdown; SecinH3 pharmacological inhibition; in vivo OVX model; RNA-sequencing; JNK and IRE1 activity assays; XBP1 splicing assay Pharmacological research Medium 36252772
2022 FE65 neuronal adaptor interacts with ARNO and forms an ARNO–ARF6–FE65 trimeric complex; FE65 potentiates ARNO-stimulated ARF6-mediated neurite outgrowth. FE65 attenuates ARNO intramolecular autoinhibitory interaction and its effect requires ARNO dimerization (monomeric ARNO mutant is not potentiated by FE65). Co-immunoprecipitation; co-localization; FE65 interaction-disrupting mutation; ARF6 activation assay; neurite outgrowth assay Open biology Medium 36168805
2023 V-ATPase V0a1 subunit interacts with ARNO in neuroendocrine cells; disruption of V0a1–ARNO interaction inhibits Arf6 activation during exocytosis, PLD activation, phosphatidic acid synthesis, and alters fusion event timing. This places V-ATPase as an upstream activator of the ARNO–Arf6–PLD1 pathway during exocytosis. Co-immunoprecipitation; interaction disruption; PLD activity assay; phosphatidic acid measurement; exocytosis timing assay; Arf6-GTP assay in neuroendocrine cells Frontiers in molecular biosciences Medium 37091866
2026 Full knockout of cytohesin-2 in mice causes perinatal lethality within 20 h of birth. Cytohesin-2 deficiency reduces Golgi volume in C2 myoblasts (restored by re-expression in an ARF-GEF-independent manner), impairs peanut agglutinin staining (galactose/N-acetyl-galactosamine reduction), and markedly reduces global protein secretion in neonatal knockout mice. Full knockout mouse; mass spectrometry-based organellar proteomics; immunofluorescence; quantitative proteomics; peanut agglutinin staining; re-expression rescue Life science alliance High 41672711

Source papers

Stage 0 corpus · 76 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nature cell biology 396 16415858
2001 Activation of ARF6 by ARNO stimulates epithelial cell migration through downstream activation of both Rac1 and phospholipase D. The Journal of cell biology 325 11481345
1998 Insulin-dependent translocation of ARNO to the plasma membrane of adipocytes requires phosphatidylinositol 3-kinase. Current biology : CB 230 9550703
1998 ARNO is a guanine nucleotide exchange factor for ADP-ribosylation factor 6. The Journal of biological chemistry 208 9417041
1998 A glutamic finger in the guanine nucleotide exchange factor ARNO displaces Mg2+ and the beta-phosphate to destabilize GDP on ARF1. The EMBO journal 164 9649435
1998 Structure of the guanine nucleotide exchange factor Sec7 domain of human arno and analysis of the interaction with ARF GTPase. Cell 162 9476900
1998 Structure of the Sec7 domain of the Arf exchange factor ARNO. Nature 154 9510256
1997 Role of protein-phospholipid interactions in the activation of ARF1 by the guanine nucleotide exchange factor Arno. The Journal of biological chemistry 150 9268368
2003 ARNO and ARF6 regulate axonal elongation and branching through downstream activation of phosphatidylinositol 4-phosphate 5-kinase alpha. Molecular biology of the cell 141 14565977
2012 Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability. Nature 140 23143332
2005 The DOCK180/Elmo complex couples ARNO-mediated Arf6 activation to the downstream activation of Rac1. Current biology : CB 130 16213822
2001 Intra-endosomal pH-sensitive recruitment of the Arf-nucleotide exchange factor ARNO and Arf6 from cytoplasm to proximal tubule endosomes. The Journal of biological chemistry 117 11278939
1998 Remodeling of the actin cytoskeleton is coordinately regulated by protein kinase C and the ADP-ribosylation factor nucleotide exchange factor ARNO. Molecular biology of the cell 114 9802902
2007 ARL4D recruits cytohesin-2/ARNO to modulate actin remodeling. Molecular biology of the cell 82 17804820
2012 Salmonella virulence effector SopE and Host GEF ARNO cooperate to recruit and activate WAVE to trigger bacterial invasion. Cell host & microbe 77 22341462
2000 The ADP ribosylation factor nucleotide exchange factor ARNO promotes beta-arrestin release necessary for luteinizing hormone/choriogonadotropin receptor desensitization. Proceedings of the National Academy of Sciences of the United States of America 70 10811902
2010 Kinetic studies of the Arf activator Arno on model membranes in the presence of Arf effectors suggest control by a positive feedback loop. The Journal of biological chemistry 66 21118813
2001 Specificities for the small G proteins ARF1 and ARF6 of the guanine nucleotide exchange factors ARNO and EFA6. The Journal of biological chemistry 62 11342560
2011 Aldolase directly interacts with ARNO and modulates cell morphology and acidic vesicle distribution. American journal of physiology. Cell physiology 59 21307348
1999 Regulation of ARNO nucleotide exchange by a PH domain electrostatic switch. Current biology : CB 58 10531036
2000 Binding of the PH and polybasic C-terminal domains of ARNO to phosphoinositides and to acidic lipids. Biochemistry 55 10801341
2003 Interaction protein for cytohesin exchange factors 1 (IPCEF1) binds cytohesin 2 and modifies its activity. The Journal of biological chemistry 53 12920129
2005 Heterotrimeric G protein-independent signaling of a G protein-coupled receptor. Direct binding of ARNO/cytohesin-2 to the carboxyl terminus of the A2A adenosine receptor is necessary for sustained activation of the ERK/MAP kinase pathway. The Journal of biological chemistry 52 16027149
2002 The N-terminal coiled coil domain of the cytohesin/ARNO family of guanine nucleotide exchange factors interacts with the scaffolding protein CASP. The Journal of biological chemistry 52 12052827
2004 Discriminatory aptamer reveals serum response element transcription regulated by cytohesin-2. Proceedings of the National Academy of Sciences of the United States of America 50 15277685
2010 Cytohesin-2/ARNO, through its interaction with focal adhesion adaptor protein paxillin, regulates preadipocyte migration via the downstream activation of Arf6. The Journal of biological chemistry 49 20525696
2011 Arf nucleotide binding site opener [ARNO] promotes sequential activation of Arf6, Cdc42 and Rac1 and insulin secretion in INS 832/13 β-cells and rat islets. Biochemical pharmacology 48 21276423
2009 GRASP and IPCEF promote ARF-to-Rac signaling and cell migration by coordinating the association of ARNO/cytohesin 2 with Dock180. Molecular biology of the cell 42 20016009
2007 The calcium-sensing receptor changes cell shape via a beta-arrestin-1 ARNO ARF6 ELMO protein network. Journal of cell science 40 17623778
1998 Overexpression of the ARF1 exchange factor ARNO inhibits the early secretory pathway and causes the disassembly of the Golgi complex. Journal of cell science 39 9788883
2022 Genome-wide CRISPR-Cas9 screening identifies the CYTH2 host gene as a potential therapeutic target of influenza viral infection. Cell reports 37 35354039
2016 Podosome assembly is controlled by the GTPase ARF1 and its nucleotide exchange factor ARNO. The Journal of cell biology 36 28007915
2013 The N termini of a-subunit isoforms are involved in signaling between vacuolar H+-ATPase (V-ATPase) and cytohesin-2. The Journal of biological chemistry 32 23288846
2003 The guanine nucleotide exchange factor ARNO mediates the activation of ARF and phospholipase D by insulin. BMC cell biology 30 12969509
2011 ARNO regulates VEGF-dependent tissue responses by stabilizing endothelial VEGFR-2 surface expression. Cardiovascular research 29 22002459
2009 Valproic acid-inducible Arl4D and cytohesin-2/ARNO, acting through the downstream Arf6, regulate neurite outgrowth in N1E-115 cells. Experimental cell research 29 19327349
2006 ARF6 activation by Galpha q signaling: Galpha q forms molecular complexes with ARNO and ARF6. Cellular signalling 27 16650966
2010 Specific motifs of the V-ATPase a2-subunit isoform interact with catalytic and regulatory domains of ARNO. Biochimica et biophysica acta 24 20153292
2018 INAVA-ARNO complexes bridge mucosal barrier function with inflammatory signaling. eLife 23 30355448
2014 Cytohesin 2/ARF6 regulates preadipocyte migration through the activation of ERK1/2. Biochemical pharmacology 21 25450674
2020 A view on the quality of diabetes care in Italy and the role of Diabetes Clinics from the 2018 ARNO Diabetes Observatory. Nutrition, metabolism, and cardiovascular diseases : NMCD 20 32998821
2014 Cytohesins/ARNO: the function in colorectal cancer cells. PloS one 20 24618737
2006 ARNO through its coiled-coil domain regulates endocytosis at the apical surface of polarized epithelial cells. The Journal of biological chemistry 20 16484220
2001 Desensitization of the luteinizing hormone/choriogonadotropin receptor in ovarian follicular membranes is inhibited by catalytically inactive ARNO(+). The Journal of biological chemistry 20 11139567
2014 The RLIP76 N-terminus binds ARNO to regulate PI 3-kinase, Arf6 and Rac signaling, cell spreading and migration. Biochemical and biophysical research communications 19 25450693
2015 RLIP76 regulates Arf6-dependent cell spreading and migration by linking ARNO with activated R-Ras at recycling endosomes. Biochemical and biophysical research communications 17 26498519
2014 Cytohesin-2 phosphorylation by protein kinase C relieves the constitutive suppression of platelet dense granule secretion by ADP-ribosylation factor 6. Journal of thrombosis and haemostasis : JTH 16 24581425
2014 Arf6 guanine nucleotide exchange factor cytohesin-2 binds to CCDC120 and is transported along neurites to mediate neurite growth. The Journal of biological chemistry 16 25326380
2007 A Role for ARF6 and ARNO in the regulation of endosomal dynamics in neurons. Traffic (Copenhagen, Denmark) 15 17897316
2021 The synaptic scaffolding protein CNKSR2 interacts with CYTH2 to mediate hippocampal granule cell development. The Journal of biological chemistry 14 34800437
2018 Pallidin is a novel interacting protein for cytohesin-2 and regulates the early endosomal pathway and dendritic formation in neurons. Journal of neurochemistry 14 30151872
2013 Fragment-based identification of a locus in the Sec7 domain of Arno for the design of protein-protein interaction inhibitors. Journal of medicinal chemistry 14 24112024
2012 Arf6 guanine-nucleotide exchange factor, cytohesin-2, interacts with actinin-1 to regulate neurite extension. Cellular signalling 14 22659138
2015 Arf6 guanine-nucleotide exchange factor cytohesin-2 regulates myelination in nerves. Biochemical and biophysical research communications 13 25824033
2007 The N-terminal coiled-coil domain of the cytohesin/ARNO family of guanine nucleotide exchange factors interacts with Galphaq. Molecular and cellular biochemistry 13 17846866
2022 Blocking the cytohesin-2/ARF1 axis by SecinH3 ameliorates osteoclast-induced bone loss via attenuating JNK-mediated IRE1 endoribonuclease activity. Pharmacological research 12 36252772
2015 ARF-GEF cytohesin-2/ARNO regulates R-Ras and α5-integrin recycling through an EHD1-positive compartment. Molecular biology of the cell 12 26378252
2004 Conformational states of the small G protein Arf-1 in complex with the guanine nucleotide exchange factor ARNO-Sec7. The Journal of biological chemistry 12 14739276
2012 Phagocytic NADPH oxidase links ARNO-Arf6 signaling pathway in glucose-stimulated insulin secretion from the pancreatic β-cell. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 11 23095975
2020 Arf6 Can Trigger Wave Regulatory Complex-Dependent Actin Assembly Independent of Arno. International journal of molecular sciences 10 32252226
2022 The adaptor SH2B1 and the phosphatase PTP4A1 regulate the phosphorylation of cytohesin-2 in myelinating Schwann cells in mice. Science signaling 8 35077201
2019 Molecular Architecture of a Network of Potential Intracellular EGFR Modulators: ARNO, CaM, Phospholipids, and the Juxtamembrane Segment. Structure (London, England : 1993) 8 31780432
2002 ARNO but not cytohesin-1 translocation is phosphatidylinositol 3-kinase-dependent in HL-60 cells. Journal of leukocyte biology 8 11927660
2022 ARNO is recruited by the neuronal adaptor FE65 to potentiate ARF6-mediated neurite outgrowth. Open biology 7 36168805
2021 Cytohesin-2 mediates group I metabotropic glutamate receptor-dependent mechanical allodynia through the activation of ADP ribosylation factor 6 in the spinal cord. Neurobiology of disease 7 34390832
2020 Autographivirinae Bacteriophage Arno 160 Infects Pectobacterium carotovorum via Depolymerization of the Bacterial O-Polysaccharide. International journal of molecular sciences 7 32365879
2021 S100A6, Calumenin and Cytohesin 2 as Biomarkers for Cutaneous Involvement in Systemic Sclerosis Patients: A Case Control Study. Journal of personalized medicine 6 34063287
2021 Initial treatment of diabetes in Italy. A nationwide population-based study from of the ARNO Diabetes Observatory. Nutrition, metabolism, and cardiovascular diseases : NMCD 6 34218990
2023 V-ATPase modulates exocytosis in neuroendocrine cells through the activation of the ARNO-Arf6-PLD pathway and the synthesis of phosphatidic acid. Frontiers in molecular biosciences 5 37091866
2020 The GEF Cytohesin-2/ARNO Mediates Resistin induced Phenotypic Switching in Vascular Smooth Muscle Cells. Scientific reports 5 32111889
2022 Cytohesin-2/ARNO: A Novel Bridge Between Cell Migration and Immunoregulation in Synovial Fibroblasts. Frontiers in immunology 3 35095899
2021 Deletion of Arno Reduces Eosinophilic Inflammation and Interleukin-5 Expression in a Murine Model of Rhinitis. Ear, nose, & throat journal 2 33393815
2005 Functional assay of ARNO and ARF6 in neurite elongation and branching. Methods in enzymology 2 16413274
2026 Cytohesin-2 is essential for the perinatal development of mice and regulates Golgi volume. Life science alliance 0 41672711
2025 G3BP1 maintains endothelial barrier integrity through dual mechanisms: direct stabilization of junction protein mRNAs and suppression of the inflammatory MYD88-ARNO-ARF6 pathway. Angiogenesis 0 40855241
1998 Human cts18.1 gene: chromosomal localization and PH-domain analysis. Genes & genetic systems 0 10085552

Missed literature

Know a paper Affinage missed for CYTH2? Flag it for the maintainers and the community.

No submissions yet.