Affinage

CYTH1

Cytohesin-1 · UniProt Q15438

Length
398 aa
Mass
46.4 kDa
Annotated
2026-06-09
40 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Cytohesin-1 (CYTH1) is a Sec7-domain guanine nucleotide exchange factor (GEF) for ARF GTPases that couples phosphoinositide 3-kinase signaling to integrin-mediated cell adhesion, cytoskeletal remodeling, and cell migration (PMID:9050849, PMID:9614087, PMID:10835351). It accelerates GDP-to-GTP exchange on ARF1, ARF3, and ARF6 in a brefeldin A-insensitive manner, with the isolated Sec7 domain acting on a broader ARF panel than the full-length protein, indicating that flanking regions tune substrate specificity (PMID:9050849, PMID:9756891); the Sec7 fold engages ARF1 through its C-terminal subdomain, and exchange requires the ARF1 N-terminal helix, switch 1 (Lys-38), and C-terminus (PMID:9653114, PMID:10212218). Membrane recruitment downstream of PI 3-kinase depends on cooperative high-affinity PI(3,4,5)P3 binding by the PH domain together with the adjacent C-terminal polybasic domain (PMID:9614087, PMID:9693361, PMID:10341214). Cytohesin-1 directly binds the integrin β2 (CD18) cytoplasmic domain and activates LFA-1-mediated adhesion through two separable mechanisms: a GEF-independent conformational activation of LFA-1 and a GEF-dependent program of cell spreading (PMID:8706128, PMID:10835351). Through these activities it drives leukocyte arrest and transendothelial migration, monocyte and HSPC adhesion and homing, CR3-dependent phagocytosis, and neutrophil ARF6-driven PLD activation, superoxide production, and degranulation (PMID:11747824, PMID:27899358, PMID:15778383, PMID:20018626). Its activity is regulated by PKCδ phosphorylation of the polybasic domain, which promotes actin cytoskeleton association, and by Fyn-mediated phosphorylation at Tyr-382, which is required for Schwann cell myelination and migration via Arf6 (PMID:11438522, PMID:23012656, PMID:23517829). A microexon-encoded PH domain variation switches PI(3,4,5)P3 versus PI(4,5)P2 selectivity to spatially restrict Arf6 signaling during RTK-driven migration (PMID:30404949). CYTH1 also supports leukemic cell adhesion, homing, and survival, where its inhibition reduces ITGB2 and MCL1 (PMID:37644132).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1996 High

    Established cytohesin-1 as a physical and functional link between an integrin cytoplasmic tail and inside-out adhesion signaling, answering how LFA-1 adhesiveness might be controlled intracellularly.

    Evidence Integrin β2 cytoplasmic domain interaction assays and overexpression/dominant-negative constructs in Jurkat cells with ICAM-1 adhesion readout

    PMID:8706128

    Open questions at the time
    • Did not define the biochemical activity of the SEC7 domain
    • Mechanism of how PH domain inhibits adhesion unresolved
  2. 1997 High

    Defined the molecular activity of cytohesin-1 as a brefeldin A-insensitive ARF-GEF, identifying the enzymatic basis for its downstream effects.

    Evidence In vitro [35S]GTPγS binding and [3H]GDP release assays with recombinant cytohesin-1 and purified ARF1/ARF3

    PMID:9050849

    Open questions at the time
    • Did not connect GEF activity to adhesion phenotype
    • ARF6 not yet tested
  3. 1998 High

    Placed PI 3-kinase upstream of cytohesin-1 and defined the lipid-binding module governing membrane recruitment, establishing the signaling logic of the pathway.

    Evidence Constitutively active PI3K and dominant-negative PH constructs with membrane fractionation and adhesion assays; biosensor affinity measurements of PH plus polybasic domain binding to PI(3,4,5)P3

    PMID:9614087 PMID:9693361

    Open questions at the time
    • In vivo PI(3,4,5)P3 dynamics not visualized at this stage
    • Whether membrane recruitment alone suffices for activation unresolved
  4. 1998 High

    Resolved the Sec7 domain structure and ARF substrate range, distinguishing intrinsic catalytic specificity from full-length regulation and showing the Sec7 domain does not bind the integrin tail directly.

    Evidence NMR solution structure with chemical shift perturbation mapping and structure-based mutagenesis; in vitro GTPγS assays across an ARF/ARL panel comparing Sec7 domain to full-length protein

    PMID:9653114 PMID:9756891

    Open questions at the time
    • Structural basis of the integrin-binding interface not identified
    • Determinants outside Sec7 that narrow specificity not mapped
  5. 1999 High

    Confirmed PI(3,4,5)P3-selective PH binding drives PI3K-dependent membrane translocation in response to RTK stimulation and mapped the ARF1 surfaces required for productive exchange.

    Evidence In vitro PH-lipid affinity assays and GFP-cytohesin-1 imaging in EGF/NGF-stimulated PC12 cells with PI3K inhibitors; ARF1/ARL1 chimera and Lys-38 mutagenesis with in vitro exchange assays

    PMID:10212218 PMID:10341214

    Open questions at the time
    • Did not address ARF6-specific recruitment
    • Effector consequences downstream of activated ARF not defined
  6. 1999 Medium

    Demonstrated a physiological requirement for cytohesin-1 in LPS-induced, PI3K- and Rho-dependent monocyte adhesion, extending its role beyond T cells.

    Evidence Antisense knockdown in THP-1/CD14 cells with Rho and PI3K inhibitors and ICAM-1 adhesion assays

    PMID:9873050

    Open questions at the time
    • Single antisense approach without genetic rescue
    • Direct molecular link to CD14 not established
  7. 2000 High

    Dissected adhesion into a GEF-independent LFA-1 conformational activation step and a GEF-dependent spreading step, clarifying how one protein controls two adhesion outputs.

    Evidence β2 tail mutants and GEF-dead E157K cytohesin-1 with in vitro exchange assays, activation-epitope detection, and adhesion/spreading assays

    PMID:10835351

    Open questions at the time
    • Identity of the spreading-relevant ARF in vivo not pinned down
    • How direct binding triggers conformational change mechanistically unclear
  8. 2000 Medium

    Showed phosphoinositides and accessory targets modulate cytohesin-1 ARF preference, adding regulatory and substrate complexity to the GEF.

    Evidence In vitro GTP-binding assays with ARF1-Ig/ARF6-Ig chimeras and added phosphoinositides; yeast two-hybrid, in vitro exchange, Sec7 mutagenesis, and COS-7 colocalization with ARD1; Golgi localization by immunofluorescence with BFA

    PMID:10748148 PMID:10772823 PMID:10848997

    Open questions at the time
    • Lipid-driven specificity switch shown only in vitro with chimeric substrates
    • Endogenous Golgi versus plasma membrane balance not reconciled across cell types
  9. 2001 High

    Identified post-translational and pathogen-driven regulation: PKCδ phosphorylation links cytohesin-1 to the actin cytoskeleton, and kaposin A hijacks its GEF activity to remodel cells.

    Evidence In vitro PKCδ kinase assay with in vivo phorbol ester phosphorylation, actin co-sedimentation, and adhesion assays; Co-IP, E157K rescue, and liposome-embedded kaposin A in vitro ARF assays with focus/stress fiber phenotypes

    PMID:11336706 PMID:11438522

    Open questions at the time
    • How actin association feeds back on GEF output not defined
    • Endogenous regulators analogous to kaposin A not identified
  10. 2001 Medium

    Separated PH-dependent firm arrest from GEF- and integrin-binding-dependent migration under flow and named ARF6 as the chemotaxis-relevant target.

    Evidence PH, GEF-dead, and β2-binding mutants in flow-based leukocyte adhesion and transendothelial migration assays with ARF6 dominant-negative rescue

    PMID:11747824

    Open questions at the time
    • Single-lab dissection without genetic knockout
    • How PH domain mediates arrest independently of GEF activity unresolved
  11. 2002 Medium

    Identified Cybr as a coiled-coil partner that enhances cytohesin-1 GEF activity, adding a protein cofactor layer to ARF activation.

    Evidence Co-IP of overexpressed proteins and in vitro ARF exchange assays with recombinant Cybr

    PMID:11867758

    Open questions at the time
    • Co-IP from overexpression without endogenous validation
    • Cellular consequence of Cybr-cytohesin coupling not defined
  12. 2003 Medium

    Linked LFA-1 signaling through cytohesin-1 to ERK activation, JAB-1 release, and Th1 differentiation, connecting adhesion machinery to downstream immune transcriptional outcomes.

    Evidence Phosphoprotein flow cytometry and dominant-negative cytohesin-1 with cytokine production assays

    PMID:14528303

    Open questions at the time
    • Dominant-negative approach without knockout
    • Direct versus indirect role in JAB-1 release not separated
  13. 2005 Medium

    Extended cytohesin-1 function to innate immune phagocytosis by showing it is required for CD14-regulated, CR3-mediated mycobacterial internalization.

    Evidence siRNA knockdown, PI3K inhibitors, and Co-IP of CR3 with cytohesin-1, plus flow cytometry phagocytosis assays

    PMID:15778383

    Open questions at the time
    • Single-lab knockdown without rescue
    • Whether GEF activity is required for phagocytosis not tested
  14. 2009 High

    Established a specific cytohesin-1/Arf6 axis driving neutrophil effector functions, linking the GEF to PLD, NADPH oxidase, and degranulation.

    Evidence SecinH3 inhibition, siRNA, and stable overexpression in PLB-985 cells with Arf6/Arf1 activation, PLD, superoxide, and granule marker assays

    PMID:20018626

    Open questions at the time
    • Spatial coupling of Arf6 to NADPH oxidase not resolved
    • In vivo neutrophil relevance not tested
  15. 2012 High

    Defined Fyn phosphorylation at Tyr-382 as an in vivo regulatory switch required for peripheral myelination, providing genetic causality in a tissue context.

    Evidence In vitro Fyn kinase assay plus Schwann cell-specific Y382F transgenic and cytohesin-1 knockout mice with peripheral nerve electron microscopy

    PMID:23012656

    Open questions at the time
    • How Y382 phosphorylation alters GEF activity mechanistically unclear
    • Upstream signal activating Fyn in Schwann cells not defined
  16. 2013 Medium

    Showed the cytohesin-1/Arf6 axis and Y382 are required for Schwann cell migration and that gain-of-function enhances myelination in vivo, consolidating the myelination mechanism.

    Evidence siRNA, SecinH3, knockout, and Y382F rescue in transwell migration assays; Schwann cell-specific transgenic overexpression with nerve morphometry and Arf6 activation assays

    PMID:23517829 PMID:23636892

    Open questions at the time
    • Effectors downstream of Arf6 in migration/myelination not identified
    • Single-lab in vivo gain-of-function
  17. 2016 High

    Demonstrated CYTH1 controls hematopoietic stem/progenitor cell adhesion and bone marrow homing, integrating integrin β1 activation with in vivo niche lodgment.

    Evidence RNAi screen and shRNA knockdown with adhesion assays, integrin β1 activation assay, xenograft transplantation, and intravital microscopy

    PMID:27899358

    Open questions at the time
    • Whether GEF activity versus integrin binding drives homing not separated
    • ARF target in HSPCs not identified
  18. 2018 High

    Revealed that a microexon-encoded PH domain difference toggles PI(3,4,5)P3 versus PI(4,5)P2 selectivity to spatially route Arf6 signaling during RTK-driven migration.

    Evidence Microexon splicing analysis, phosphoinositide binding assays, live-cell imaging of GFP isoforms, and HGF/Met migration assays with isoform-specific knockdown and rescue

    PMID:30404949

    Open questions at the time
    • Regulation of microexon inclusion across tissues not defined
    • Whether other CYTH paralogs share this switch not addressed
  19. 2023 Medium

    Implicated CYTH1 in leukemic cell adhesion, homing, engraftment, and survival, nominating it as a therapeutic target whose inhibition lowers ITGB2 and MCL1.

    Evidence shRNA knockdown and SecinH3 inhibition in AML cell lines and xenografts with proliferation, apoptosis, and Western blot readouts, plus venetoclax synergy

    PMID:37644132

    Open questions at the time
    • Mechanism linking CYTH1 to MCL1 regulation unresolved
    • Single-lab pharmacology without genetic patient validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How phosphorylation states, lipid selectivity, and accessory partners are integrated to select between specific ARF substrates and downstream effectors in a given cellular context remains unresolved.
  • No unified structural model coupling PH-domain lipid sensing to Sec7 substrate selection
  • Endogenous effectors downstream of Arf1 versus Arf6 in distinct cell types not fully mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-5653656 Vesicle-mediated transport 3
Partners
ARD1ARF1ARF6FYNITGAMITGB2PRKCDPSCDBP

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Cytohesin-1 specifically interacts with the intracellular portion of the integrin β2 chain (CD18) and overexpression of full-length cytohesin-1 or its SEC7 domain induces β2 integrin-dependent binding of Jurkat cells to ICAM-1, while expression of the isolated PH domain inhibits T cell receptor-stimulated adhesion. Co-interaction assay with integrin β2 cytoplasmic domain; overexpression and dominant-negative studies in Jurkat cells measuring ICAM-1 adhesion Cell High 8706128
1997 Cytohesin-1 functions as a guanine nucleotide-exchange protein (GEP) for ARF GTPases, accelerating GDP-to-GTP exchange on ARF1 and ARF3 purified from bovine brain; this GEP activity is not inhibited by brefeldin A, distinguishing it from BFA-sensitive ARF-GEPs. In vitro GEP assay with recombinant cytohesin-1 (expressed in E. coli) and purified ARF; [35S]GTPγS binding and [3H]GDP release assays Proceedings of the National Academy of Sciences of the United States of America High 9050849
1998 Constitutively active PI 3-kinase is sufficient to activate Jurkat cell adhesion to ICAM-1 and induces membrane recruitment of cytohesin-1; this effect requires the cytohesin-1 PH domain, placing PI 3-kinase upstream of cytohesin-1 in the β2 integrin inside-out signaling pathway. Overexpression of constitutively active PI 3-kinase; dominant-negative PH domain constructs; membrane fractionation to assess cytohesin-1 localization; adhesion assays The Journal of biological chemistry High 9614087
1998 Both the PH domain and the adjacent C-terminal polybasic (c) domain of cytohesin-1 are required together for high-affinity (100 nM) binding to PI(3,4,5)P3 and for plasma membrane association and biological function; the isolated PH domain has substantially lower affinity (~2–3 µM) for PI(3,4,5)P3. Biosensor affinity measurements; deletion/chimeric mutant expression in Jurkat cells; membrane association assays; functional adhesion assays Molecular biology of the cell High 9693361
1998 NMR solution structure of the cytohesin-1 Sec7 domain reveals 10 α-helices forming a unique fold; ARF1 binding occurs through a large surface on the C-terminal subdomain involving hydrophobic and polar residues; structure-based mutagenesis identified residues critical for ARF binding and nucleotide exchange. However, the Sec7 domain and the β2 integrin cytoplasmic domain do not interact in solution phase. NMR spectroscopy; 1H-15N and 1H-13C chemical shift perturbation mapping; structure-based mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 9653114
1998 The cytohesin-1 Sec7 domain catalyzes guanine nucleotide exchange on ARFs 1, 5, and 6, yeast ARFs 1–3, and ARD1; full-length cytohesin-1 shows narrower substrate specificity (active on ARF1, ARF3, and ARD1 but not ARF5/6), indicating that regions outside the Sec7 domain contribute to substrate specificity. Neither acts on ARF-like (ARL) proteins. In vitro GTPγS binding assays with purified recombinant proteins; comparison of Sec7 domain alone vs. full-length cytohesin-1 across a panel of ARF/ARL substrates The Journal of biological chemistry High 9756891
1999 Cytohesin-1 PH domain binds the inositol head group of PI(3,4,5)P3 (as IP4) with >200-fold higher affinity than PI(4,5)P2 or PI(3,4)P2 in vitro; EGF- or NGF-stimulated translocation of GFP-cytohesin-1 from cytosol to plasma membrane in PC12 cells requires PI 3-kinase activity and an intact PH domain. In vitro PH domain-lipid binding assays; GFP-cytohesin-1 live-cell confocal microscopy in PC12 cells; wortmannin/LY294002 inhibition; dominant-negative p85 co-expression Journal of cell science High 10341214
1999 Structural elements in ARF1 required for functional interaction with cytohesin-1 include the N-terminal α-helix (residues 1–13), switch 1 region (residues 28–50, including Lys-38), and C-terminal region (last 42 amino acids); replacing Lys-38 with Gln abolishes the interaction with both cytohesin-1 and its Sec7 domain. ARF1/ARL1 chimeric protein panel; site-directed mutagenesis; in vitro [35S]GTPγS binding assays The Journal of biological chemistry High 10212218
1999 Cytohesin-1 is required for LPS-induced β2 integrin (LFA-1)-mediated monocyte adherence to ICAM-1 downstream of CD14, Rho, and PI 3-kinase; antisense knockdown of cytohesin-1 abrogates LPS-induced adherence without affecting LFA-1 surface expression. Cytohesin-1 antisense oligonucleotides in THP-1/CD14 cells; PI 3-kinase inhibitors; Toxin B (Rho inhibitor); ICAM-1 adhesion assays The Journal of biological chemistry Medium 9873050
2000 Cytohesin-1 regulates β2 integrin adhesion through two separable mechanisms: (1) direct interaction with the LFA-1 β2 cytoplasmic domain activates an extracellular epitope of LFA-1 independent of ARF-GEF activity; (2) ARF-GEF activity is required for LFA-1-mediated cell spreading on ICAM-1. A GEF-dead mutant of cytohesin-1 blocks spreading but not initial LFA-1 activation. Mutational analysis of β2 cytoplasmic domain; cytohesin-1 GEF-dead mutant (E157K); in vitro ARF GDP-GTP exchange assays; LFA-1 activation epitope detection; cell adhesion and spreading assays The EMBO journal High 10835351
2000 PI(3,4,5)P3 differentially regulates cytohesin-1 GEF specificity: it suppresses cytohesin-1-dependent GTP binding to ARF6-Ig chimeras while enhancing GTP binding to ARF1-Ig chimeras, thereby switching ARF substrate specificity of cytohesin-1. In vitro GTP-binding assays using immunoprecipitated ARF1-Ig and ARF6-Ig chimeras from mammalian cells; addition of purified phosphoinositides European journal of biochemistry Medium 10848997
2000 Cytohesin-1 specifically accelerates GTPγS binding to ARD1 (a 64-kDa lysosomal/Golgi GTPase) but not cytohesin-2; the specificity is determined by residue 30 in the Sec7 domain and the ARD1 effector region; in COS-7 cells, overexpressed ARD1 and cytohesin-1 partially colocalize. Yeast two-hybrid screen (ARD1 as bait); in vitro [35S]GTPγS binding assays; Sec7 domain point mutagenesis; confocal fluorescence microscopy of co-transfected COS-7 cells The Journal of biological chemistry Medium 10748148
2000 B2-1/cytohesin-1 localizes to the Golgi complex (not primarily the plasma membrane) under endogenous expression conditions; this Golgi association is disrupted by brefeldin A; overexpression of GFP-B2-1 shows Golgi targeting and excessive overexpression causes partial Golgi dispersion. Immunofluorescence localization; brefeldin A treatment; transient transfection of GFP-tagged B2-1; confocal microscopy Experimental cell research Medium 10772823
2001 Protein kinase Cδ phosphorylates a serine/threonine motif within the C-terminal polybasic domain of cytohesin-1 in vitro; phorbol ester stimulation also induces phosphorylation of these residues in vivo; PKC-phosphorylated cytohesin-1 associates tightly with the actin cytoskeleton and phosphorylation is required for maximal LFA-1-mediated Jurkat cell adhesion to ICAM-1. In vitro kinase assay with purified PKCδ; phorbol ester stimulation in vivo; co-sedimentation with actin cytoskeleton; site-directed mutagenesis; adhesion assays The Journal of biological chemistry High 11438522
2001 Human herpesvirus 8 kaposin A directly interacts with cytohesin-1 and recruits it to the membrane; this interaction mediates kaposin A-induced focus formation, stress fiber dissolution, and ERK-1/2 MAP kinase activation; these effects are reversed by the GEF-dead cytohesin-1 E157K mutant; liposome-embedded kaposin A specifically stimulates cytohesin-1-dependent GTP binding to myristoylated ARF1 in vitro. Co-immunoprecipitation; dominant-negative GEF mutant (E157K) rescue; in vitro ARF GTP-binding assay with liposome-embedded kaposin A; focus formation and stress fiber assays Molecular cell High 11336706
2001 Cytohesin-1 overexpression increases LFA-1-dependent leukocyte arrest triggered by chemokines on cytokine-activated endothelium; the PH domain (not GEF activity) mediates firm arrest, while both LFA-1 interaction and GEF activity are required for shape change and transendothelial chemotaxis; ARF6 (but not ARF1) participates as downstream GEF target in chemotaxis. Overexpression and dominant-negative constructs (PH domain, GEF-dead mutant, β2 cytoplasmic domain mutant) in flow-based leukocyte adhesion assays on endothelium; transendothelial migration assays; ARF6 dominant-negative rescue Current biology : CB Medium 11747824
2002 Cybr (a cytokine-inducible protein related to GRASP) physically interacts with cytohesin-1 via coiled-coil domain interactions and enhances cytohesin-1-catalyzed GTPγS binding to ARF in vitro. Co-immunoprecipitation of overexpressed proteins from 293T cells; in vitro ARF GEP activity assay with recombinant Cybr Proceedings of the National Academy of Sciences of the United States of America Medium 11867758
2003 LFA-1 activation induces phosphorylation of the β2 integrin chain, releases JAB-1, and mediates ERK1/2 signaling through cytohesin-1; dominant-negative cytohesin-1 inhibits IL-2 production and impairs Th1 differentiation. Intracellular phosphoprotein staining with 13-dimensional flow cytometry; dominant-negative cytohesin-1 expression; cytokine production assays Nature immunology Medium 14528303
2005 CD14-regulated complement receptor 3 (CR3/Mac-1)-dependent phagocytosis of mycobacteria requires cytohesin-1; cytohesin-1 physically associates with CR3 upon stimulation with mycobacterial surface components; knockdown of cytohesin-1 specifically abrogates CD14-regulated CR3-mediated BCG internalization. siRNA knockdown of cytohesin-1; PI3K inhibitors; blocking antibodies; flow cytometry phagocytosis assay; co-immunoprecipitation of CR3 and cytohesin-1 Journal of immunology Medium 15778383
2009 Cytohesin-1 specifically activates Arf6 (but not Arf1) in fMLP-stimulated human neutrophils; cytohesin-1/Arf6 signaling drives phospholipase D activation, NADPH oxidase-dependent superoxide production, and degranulation; SecinH3 (selective cytohesin Sec7 inhibitor) blocks these responses, as does cytohesin-1 siRNA knockdown. SecinH3 pharmacological inhibition; siRNA knockdown; stable overexpression in PLB-985 cells; Arf6 and Arf1 activation assays; PLD activity assay; superoxide production assay; surface granule marker expression by flow cytometry Journal of immunology High 20018626
2012 The Src-family kinase Fyn phosphorylates cytohesin-1 at tyrosine 382 (Y382); this phosphorylation is required for full myelination by Schwann cells. Transgenic mice expressing a Schwann cell-specific Y382F phosphorylation-deficient cytohesin-1 show delayed myelination and reduced myelin thickness similar to cytohesin-1 knockout mice. In vitro kinase assay (Fyn + cytohesin-1); phosphorylation-deficient transgenic mice (Y382F, Schwann cell-specific); cytohesin-1 knockout mice; electron microscopy of peripheral nerves Science signaling High 23012656
2013 Cytohesin-1 and its downstream GTPase Arf6 are required for peripheral neuronal conditioned medium-stimulated migration of primary Schwann cells; the Y382 residue (Fyn phosphorylation site) is required for migration since Y382F cytohesin-1 fails to rescue migration in siRNA-transfected cells. siRNA knockdown of cytohesin-1 and Arf6; SecinH3 inhibitor; cytohesin-1 knockout Schwann cells; reintroduction of siRNA-resistant wild-type vs. Y382F cytohesin-1; transwell migration assay Cellular signalling Medium 23517829
2013 Schwann cell-specific overexpression of wild-type cytohesin-1 in transgenic mice produces enhanced myelin thickness in peripheral nerves and elevated downstream Arf6 activation, confirming cytohesin-1 promotes myelination in vivo through the cytohesin-1/Arf6 signaling axis. Schwann cell-specific transgenic overexpression of cytohesin-1; electron microscopy morphometry of peripheral nerves; Arf6 activation assay Journal of molecular neuroscience Medium 23636892
2016 CYTH1 knockdown disrupts adhesion of human cord blood hematopoietic stem and progenitor cells (HSPCs) to mesenchymal stroma cells, fibronectin, and ICAM-1/2, reduces integrin β1 activation, impairs bone marrow homing after transplantation into immunodeficient mice, and impairs HSPC lodgment in the marrow niche as shown by intravital microscopy. RNAi screen; shRNA knockdown; adhesion assays; integrin β1 activation assay; xenograft transplantation; intravital microscopy Blood High 27899358
2018 A microexon-encoded triglycine vs. diglycine difference in the cytohesin-1 PH domain determines differential phosphoinositide affinity (triglycine for PI(4,5)P2, diglycine for PI(3,4,5)P3); this distinction produces distinct subcellular localizations (triglycine to plasma membrane, diglycine to leading edge) and controls Met RTK-dependent cell migration, where the diglycine/PI(3,4,5)P3-binding isoform is specifically required. Alternative splicing microexon analysis; phosphoinositide binding assays; live-cell imaging of GFP-tagged isoforms; HGF/Met-stimulated migration assays; isoform-specific knockdown and rescue The Journal of cell biology High 30404949
2023 CYTH1 depletion or inhibition with SecinH3 inhibits adhesion, migration, homing, and engraftment of AML leukemic cells in vivo; targeting CYTH1 suppresses integrin-associated adhesion signaling by reducing ITGB2 expression and reduces anti-apoptotic MCL1; SecinH3 synergizes with BCL2-inhibitor venetoclax in ABT-199-resistant AML cells. CYTH1 shRNA knockdown; SecinH3 pharmacological inhibition; AML cell line proliferation and apoptosis assays; AML xenograft mouse model; Western blotting for signaling components Acta pharmacologica Sinica Medium 37644132

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Alpha L beta 2 integrin/LFA-1 binding to ICAM-1 induced by cytohesin-1, a cytoplasmic regulatory molecule. Cell 386 8706128
2003 Leukocyte functional antigen 1 lowers T cell activation thresholds and signaling through cytohesin-1 and Jun-activating binding protein 1. Nature immunology 171 14528303
1997 Cytohesin-1, a cytosolic guanine nucleotide-exchange protein for ADP-ribosylation factor. Proceedings of the National Academy of Sciences of the United States of America 131 9050849
1998 Phosphoinositide 3-OH kinase activates the beta2 integrin adhesion pathway and induces membrane recruitment of cytohesin-1. The Journal of biological chemistry 119 9614087
2000 Cytohesin-1 regulates beta-2 integrin-mediated adhesion through both ARF-GEF function and interaction with LFA-1. The EMBO journal 111 10835351
2001 Signaling by human herpesvirus 8 kaposin A through direct membrane recruitment of cytohesin-1. Molecular cell 92 11336706
2000 Similarities in function and gene structure of cytohesin-4 and cytohesin-1, guanine nucleotide-exchange proteins for ADP-ribosylation factors. The Journal of biological chemistry 79 10652308
1998 The PH domain and the polybasic c domain of cytohesin-1 cooperate specifically in plasma membrane association and cellular function. Molecular biology of the cell 79 9693361
1999 Monocyte adherence induced by lipopolysaccharide involves CD14, LFA-1, and cytohesin-1. Regulation by Rho and phosphatidylinositol 3-kinase. The Journal of biological chemistry 78 9873050
2005 Cross-talk between CD14 and complement receptor 3 promotes phagocytosis of mycobacteria: regulation by phosphatidylinositol 3-kinase and cytohesin-1. Journal of immunology (Baltimore, Md. : 1950) 74 15778383
1999 EGF-and NGF-stimulated translocation of cytohesin-1 to the plasma membrane of PC12 cells requires PI 3-kinase activation and a functional cytohesin-1 PH domain. Journal of cell science 56 10341214
2001 Cytohesin-1 is a dynamic regulator of distinct LFA-1 functions in leukocyte arrest and transmigration triggered by chemokines. Current biology : CB 47 11747824
2012 Phosphorylation of cytohesin-1 by Fyn is required for initiation of myelination and the extent of myelination during development. Science signaling 44 23012656
2002 Cybr, a cytokine-inducible protein that binds cytohesin-1 and regulates its activity. Proceedings of the National Academy of Sciences of the United States of America 44 11867758
1998 Guanine nucleotide exchange on ADP-ribosylation factors catalyzed by cytohesin-1 and its Sec7 domain. The Journal of biological chemistry 41 9756891
1998 Solution structure of the cytohesin-1 (B2-1) Sec7 domain and its interaction with the GTPase ADP ribosylation factor 1. Proceedings of the National Academy of Sciences of the United States of America 34 9653114
2001 Actin cytoskeletal association of cytohesin-1 is regulated by specific phosphorylation of its carboxyl-terminal polybasic domain. The Journal of biological chemistry 31 11438522
2009 Cytohesin-1 regulates the Arf6-phospholipase D signaling axis in human neutrophils: impact on superoxide anion production and secretion. Journal of immunology (Baltimore, Md. : 1950) 26 20018626
2011 Cytohesin-1 regulates fMLF-mediated activation and functions of the β2 integrin Mac-1 in human neutrophils. Journal of leukocyte biology 25 21233413
2018 HGF-induced migration depends on the PI(3,4,5)P3-binding microexon-spliced variant of the Arf6 exchange factor cytohesin-1. The Journal of cell biology 23 30404949
2000 Phosphoinositides determine specificity of the guanine-nucleotide exchange activity of cytohesin-1 for ADP-ribosylation factors derived from a mammalian expression system. European journal of biochemistry 22 10848997
2011 Cytohesin-1 regulates human blood neutrophil adhesion to endothelial cells through β2 integrin activation. Molecular immunology 20 21511340
2016 Cytohesin 1 regulates homing and engraftment of human hematopoietic stem and progenitor cells. Blood 18 27899358
2023 Separation and Purification of Antioxidant Peptide from Fermented Whey Protein by Lactobacillus rhamnosus B2-1. Food science of animal resources 15 36789200
2000 Specific functional interaction of human cytohesin-1 and ADP-ribosylation factor domain protein (ARD1). The Journal of biological chemistry 14 10748148
2011 Inhibition of cytohesin-1 by siRNA leads to reduced IGFR signaling in prostate cancer. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 12 21670894
1999 Structural elements of ADP-ribosylation factor 1 required for functional interaction with cytohesin-1. The Journal of biological chemistry 10 10212218
2024 Novel Antioxidant Peptides from Fermented Whey Protein by Lactobacillus rhamnosus B2-1: Separation and Identification by in Vitro and in Silico Approaches. Journal of agricultural and food chemistry 9 39392363
2023 Targeting cytohesin-1 suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199. Acta pharmacologica Sinica 9 37644132
2014 Identification of the mulberry genes involved in ethylene biosynthesis and signaling pathways and the expression of MaERF-B2-1 and MaERF-B2-2 in the response to flooding stress. Functional & integrative genomics 9 25231943
2013 In vivo expression of the Arf6 Guanine-nucleotide exchange factor cytohesin-1 in mice exhibits enhanced myelin thickness in nerves. Journal of molecular neuroscience : MN 8 23636892
2002 ARNO but not cytohesin-1 translocation is phosphatidylinositol 3-kinase-dependent in HL-60 cells. Journal of leukocyte biology 8 11927660
2001 Characterization of cytohesin-1 monoclonal antibodies: expression in neutrophils and during granulocytic maturation of HL-60 cells. Journal of immunological methods 8 11226470
2000 B2-1, a Sec7- and pleckstrin homology domain-containing protein, localizes to the Golgi complex. Experimental cell research 8 10772823
1993 Assignment of human B2-1 gene (D17S811E) to chromosome 17qter by PCR analysis of somatic cell hybrids and fluorescence in situ hybridization. Cytogenetics and cell genetics 8 8449036
2013 Signaling through Arf6 guanine-nucleotide exchange factor cytohesin-1 regulates migration in Schwann cells. Cellular signalling 7 23517829
2000 Cloning and characterization of the promoter of murine cytohesin-1 gene. Biochimica et biophysica acta 4 10978522
2005 Cytohesin-1: structure, function, and ARF activation. Methods in enzymology 3 16413269
2017 Data on the effect of knockout of cytohesin-1 in myelination-related protein kinase signaling. Data in brief 1 29022003
2024 A natural loss-of-function deletion of the cytohesin 1 (Cyth1) gene in BALB/cByJ mice does not impact cardiomyocyte polyploidy. Scientific reports 0 38858421

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