Affinage

ROBO4

Roundabout homolog 4 · UniProt Q8WZ75

Length
1007 aa
Mass
107.5 kDa
Annotated
2026-04-28
90 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ROBO4 is an endothelial cell-specific transmembrane receptor that functions as a master regulator of vascular integrity, suppressing pathological angiogenesis, vascular permeability, and endothelial inflammation. ROBO4 maintains barrier function through multiple convergent mechanisms: it recruits paxillin/Hic-5 and the Arf-GAP GIT1 to block Arf6 and Rac1 activation, thereby suppressing protrusive activity (PMID:19855388); it signals through the Netrin receptor UNC5B to counteract VEGFR2-Y949 phosphorylation independently of its own cytoplasmic domain (PMID:27882935, PMID:21238923); and it forms a complex with TRAF7 to promote IQGAP1 ubiquitination, dampening RAC1 and NF-κB/COX-2 inflammatory signaling while stabilizing VE-cadherin at endothelial junctions (PMID:30510113, PMID:38762541). Beyond its vascular roles, ROBO4 anchors hematopoietic stem cells to bone marrow niches cooperatively with CXCR4 (PMID:21211783), and loss-of-function ROBO4 variants segregate with bicuspid aortic valve and thoracic aortic aneurysm in human families (PMID:30455415).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    Identification of ROBO4 as an endothelial-specific Robo family member that binds Slit and inhibits endothelial migration established it as a candidate vascular guidance receptor, answering whether Robo-Slit signaling operates in endothelium.

    Evidence Heterologous expression migration assays, Slit-binding assays, and co-immunoprecipitation with actin regulator Mena in endothelial cells

    PMID:12941633

    Open questions at the time
    • Whether Slit is the physiological ligand for Robo4 remained disputed
    • Downstream signaling cascade uncharacterized
  2. 2004 Medium

    Functional evidence that soluble Robo4 ectodomain inhibits angiogenesis in vivo, coupled with failure to detect Slit1-3 binding to Robo4 by BiaCore, raised the question of whether Robo4 uses an alternative ligand.

    Evidence In vivo sponge angiogenesis model, rat aortic ring assay, BiaCore direct binding analysis

    PMID:15486058

    Open questions at the time
    • Identity of the Robo4 extracellular ligand unresolved
    • Single lab observation of no Slit binding contradicted other reports
  3. 2006 Medium

    Demonstration that zebrafish Robo4 activates Cdc42 and Rac1 for angioblast guidance revealed that Robo4 can act as a pro-migratory signal, contrasting with its anti-migratory role described in mammalian cells.

    Evidence Morpholino knockdown in zebrafish, Rho GTPase pull-down assays

    PMID:16481322

    Open questions at the time
    • Context-dependent vs. species-dependent signaling not resolved
    • Mammalian Robo4 GTPase regulation appeared opposite
  4. 2008 High

    Two key advances defined Robo4's signaling outputs: Slit2-Robo4 blocks VEGF-induced migration and permeability by suppressing Src kinase (with Robo4 KO mice showing vascular disease), while Robo4 heterodimerizes with Robo1 and signals through WASP/N-WASP actin nucleators for filopodia formation.

    Evidence Robo4 knockout mouse retinal/choroidal disease models, Src kinase assays, yeast two-hybrid/GST pulldown for WASP interaction, siRNA epistasis for Robo1 requirement

    PMID:18345009 PMID:18948384

    Open questions at the time
    • How Src suppression and WASP activation are coordinated was unclear
    • Whether Robo1-Robo4 heterodimer forms in vivo remained unresolved
  5. 2009 High

    The core intracellular mechanism was elucidated: Robo4 binds paxillin/Hic-5 to recruit Arf-GAP GIT1, inactivating Arf6 and consequently Rac1, explaining how Slit2-Robo4 suppresses protrusive activity and neovascularization.

    Evidence Co-immunoprecipitation, Arf6 activation assays, in vivo retinal vascular disease phenocopy by Arf6 inhibition

    PMID:19855388

    Open questions at the time
    • Whether paxillin-GIT1 pathway accounts for all Robo4 barrier function or operates alongside other pathways
    • No structural data for Robo4-paxillin interaction
  6. 2010 High

    Translational significance was established when Slit2-Robo4 vascular barrier strengthening increased survival in sepsis and influenza models, while genetic dissection showed endothelial Robo4 (not Robo1) restricts VEGFR2/Src/FAK signaling to limit vessel growth.

    Evidence Mouse sepsis/endotoxemia/influenza survival models, conditional Robo4 vs Robo1 KO mammary gland angiogenesis

    PMID:20375003 PMID:20498081

    Open questions at the time
    • Therapeutic window for Slit2 administration undefined
    • Relative contributions of Src suppression vs Arf6 suppression not separated
  7. 2011 High

    The extracellular signaling partner UNC5B was identified, showing Robo4 maintains vascular integrity by binding UNC5B to inhibit VEGF signaling, while a parallel discovery revealed Robo4 anchors HSCs to bone marrow niches cooperatively with CXCR4.

    Evidence Robo4 extracellular domain interaction screen, UNC5B function-blocking antibodies, Robo4-/- HSC transplantation and mobilization assays with Cxcr4 epistasis

    PMID:21211783 PMID:21238923

    Open questions at the time
    • How UNC5B relays the Robo4 signal to VEGFR2 mechanistically
    • Whether HSC-intrinsic or endothelial Robo4 dominates niche anchoring
  8. 2012 Medium

    Robo4 knockdown in retinal endothelial cells revealed dependence of tight junction protein levels (ZO-1, occludin) and actin organization on Robo4 via a LIMK/cofilin pathway, extending barrier signaling beyond Rac1/Arf6.

    Evidence siRNA knockdown, RITC-dextran permeability, Western blot for tight junction and LIMK/cofilin proteins

    PMID:23163536

    Open questions at the time
    • Whether LIMK/cofilin acts downstream of Arf6 or independently not resolved
    • Replicated in one cell type only
  9. 2013 Medium

    Robo4 was shown to suppress lymphangiogenesis by inducing VEGFR-3 internalization, and to repress endothelial inflammation via Pyk2-NF-κB inhibition, while SLIT3 from pericytes was identified as a guidance cue acting through endothelial ROBO4 for vascular network assembly.

    Evidence VEGFR-3 internalization and PI3K/Akt assays, NF-κB/Pyk2 signaling analysis with siRNA, in vivo xenograft vascular formation

    PMID:24090675 PMID:24272999 PMID:24708522

    Open questions at the time
    • Whether VEGFR-3 internalization and Pyk2 suppression share upstream mechanism
    • SLIT3 vs SLIT2 selectivity for ROBO4 not settled
  10. 2016 High

    A decisive structure-function experiment showed the Robo4 cytoplasmic domain is dispensable: truncated Robo4 lacking its intracellular region fully rescues permeability and neovascularization defects, signaling instead through UNC5B to block VEGFR2-Y949 phosphorylation.

    Evidence Transgenic Robo4ΔCD mice, oxygen-induced retinopathy model, VEGFR2-Y949 phosphorylation analysis

    PMID:27882935

    Open questions at the time
    • How paxillin-Arf6 intracellular signaling reconciles with cytoplasmic-domain dispensability
    • Whether all Robo4 functions (e.g., HSC anchoring, inflammation) are also cytoplasmic-domain-independent
  11. 2018 Medium

    Annexin A2 was identified as an additional Robo4 ligand engaging the paxillin-ARF6 pathway at the blood-brain barrier, ROBO4 variants were linked to bicuspid aortic valve/aortic aneurysm in human families with functional validation, and ETV2-TET1/TET2 complexes were shown to demethylate the Robo4 promoter for endothelial-specific expression.

    Evidence ANXA2 KO mice with Robo4-ARF6 signaling analysis; targeted sequencing in families plus endothelial barrier assays with mutant ROBO4; bisulfite sequencing with ETV2-TET1/2 co-IP

    PMID:29618782 PMID:29786451 PMID:30455415

    Open questions at the time
    • ANXA2-Robo4 binding interface not mapped
    • Penetrance and mechanism of ROBO4 variants in aortic disease require larger cohorts
    • Whether ETV2-TET pathway is the sole driver of Robo4 endothelial specificity
  12. 2019 High

    TRAF7 was identified as a Robo4 cytoplasmic binding partner that stabilizes VE-cadherin at junctions, establishing a TRAF7-dependent branch of Robo4 barrier signaling distinct from the paxillin-Arf6 axis.

    Evidence Reciprocal co-immunoprecipitation, domain mapping, TRAF7 gain/loss-of-function, VE-cadherin localization, Robo4-/- endotoxemia model

    PMID:30510113

    Open questions at the time
    • Whether TRAF7 E3 ligase activity is required for VE-cadherin stabilization was answered later but not in this study
    • Relationship between TRAF7 and UNC5B pathways unknown
  13. 2022 Medium

    The mechanism controlling Robo4 surface levels was identified: ADAM10/ADAM17 constitutively shed the Robo4 ectodomain, while Slit3 induces Robo4 endocytosis to protect it from shedding, providing a feedback mechanism that enhances signaling.

    Evidence ADAM10/17 inhibitor and siRNA, Robo4 shedding quantification, Slit3-induced endocytosis assays

    PMID:35288626

    Open questions at the time
    • Whether ADAM shedding regulates Robo4 in vivo not tested
    • Whether soluble Robo4 acts as a true decoy receptor in physiological conditions
  14. 2023 High

    Transcriptional regulation of Robo4 was further defined: ALK5-SMAD2/3 positively and ALK1-SMAD1/5 negatively control Robo4 expression, and endothelial-specific Robo4 overexpression reduced mortality in endotoxemia and SARS-CoV-2 infection models.

    Evidence ALK1 inhibitor screening, SMAD pathway analysis, endothelial-specific Robo4 transgenic mice, LPS and SARS-CoV-2 models

    PMID:36634143

    Open questions at the time
    • Whether TGF-β pathway regulation of Robo4 is direct or indirect through GABP/HDAC3
    • Long-term effects of Robo4 overexpression on normal vasculature
  15. 2024 High

    The ROBO4-TRAF7-IQGAP1 complex was defined: TRAF7 ubiquitinates IQGAP1 in a ROBO4-dependent manner to suppress prolonged RAC1 activation and NF-κB/COX-2 inflammatory signaling, while separately USP5 was identified as a deubiquitinase that stabilizes ROBO4 protein.

    Evidence Co-IP for trimeric complex, IQGAP1 ubiquitination assay, RAC1 activity assay, Robo4-/- arthritis/edema models; USP5-ROBO4 deubiquitination assay

    PMID:38735506 PMID:38762541

    Open questions at the time
    • Whether USP5 regulation of ROBO4 stability is relevant in vascular endothelium in vivo
    • Structural basis for TRAF7-mediated IQGAP1 ubiquitination unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include how the cytoplasmic-domain-dispensable UNC5B pathway reconciles with documented intracellular signaling through paxillin-GIT1 and TRAF7-IQGAP1, whether distinct ligands (Slit2, Slit3, ANXA2) activate distinct downstream branches, and the structural basis for ROBO4-UNC5B interaction.
  • No structural model for any Robo4 complex
  • Context-dependent pro- vs anti-migratory signaling not mechanistically reconciled
  • Relative physiological importance of Slit2, Slit3, and ANXA2 as Robo4 ligands unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0060089 molecular transducer activity 4
Localization
GO:0005886 plasma membrane 7
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 4 R-HSA-1266738 Developmental Biology 3
Partners
GIT1IQGAP1MENAPXNROBO1TRAF7UNC5BWAS
Complex memberships
Robo1-Robo4 heterodimerRobo4-TRAF7-IQGAP1Robo4-UNC5BRobo4-paxillin/Hic-5-GIT1

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Robo4 is an endothelial-specific Robo family member that binds Slit and inhibits endothelial cell migration; immunoprecipitation showed Robo4 binds the actin regulatory protein Mena, a known effector of Robo-Slit signaling. Heterologous expression migration assay, immunoprecipitation, Slit-binding assay Developmental biology High 12941633
2008 Slit2 activation of Robo4 inhibits VEGF-165-induced endothelial migration, tube formation, and vascular permeability in vitro, and pathologic angiogenesis/vascular leak in vivo, by blocking Src family kinase activation; Robo4 knockout mice show enhanced retinal and choroidal vascular disease. In vitro migration/permeability assays, Src kinase activity assay, Robo4 knockout mouse models of retinal and choroidal vascular disease Nature medicine High 18345009
2008 Robo4 interacts with WASP (Wiskott-Aldrich syndrome protein), N-WASP, and WASP-interacting protein actin-nucleating complex via its intracellular domain; Robo4 forms a heterodimeric complex with Robo1, and Robo4-induced filopodia formation requires Robo1, suggesting a Robo1/Robo4 heterodimer signals through actin nucleation-promoting factors to regulate endothelial migration. Yeast 2-hybrid, GST pulldown, siRNA knockdown, co-immunoprecipitation, GFP-Robo4 transfection imaging FASEB journal High 18948384
2009 Slit2-Robo4 signaling maintains vascular stability by directly interacting with intracellular adaptor protein paxillin (and its paralogue Hic-5) at the cell surface, which recruits the Arf-GAP GIT1 to block activation of the small GTPase Arf6 and subsequently Rac1, thereby suppressing cellular protrusive activity underlying neovascularization and vascular leak. Co-immunoprecipitation, biochemical fractionation, Arf6 activation assay, in vivo Arf6 inhibition in retinal vascular disease models Nature cell biology High 19855388
2010 Slit2 activation of endothelial Robo4 strengthens the vascular barrier and reduces vascular permeability in lung and other organs, increasing survival in mouse models of bacterial endotoxin exposure, polymicrobial sepsis, and H5N1 influenza by blunting the host vascular response to the cytokine storm. In vivo vascular permeability assays, mouse models of endotoxemia, sepsis, and influenza; Robo4-dependent pathway activation Science translational medicine High 20375003
2011 Robo4 maintains vessel integrity and inhibits VEGF signaling by binding directly to UNC5B (a vascular Netrin receptor) via its extracellular domain; soluble Robo4 inhibits VEGF-induced permeability in wild-type but not UNC5B-blocked mice, placing Robo4 upstream of UNC5B in suppressing VEGFR signaling. Protein-protein interaction screen with Robo4 extracellular domain, function-blocking monoclonal antibodies, Robo4-/- rescue experiments, vascular permeability assays Developmental cell High 21238923
2011 Robo4 functions to anchor hematopoietic stem cells (HSCs) to bone marrow niches; Robo4-deficient HSCs show poor BM localization and reduced long-term reconstitution. Cxcr4 is upregulated in Robo4-/- HSCs to compensate, and combined inhibition of both Cxcr4 and Robo4 is required for efficient HSC mobilization. Robo4 knockout mice, transplantation assays, HSC localization/mobilization studies, flow cytometry, genetic epistasis (Cxcr4/Robo4 double manipulation) Cell stem cell High 21211783
2011 Robo4 regulates radial migration of newborn neurons in developing neocortex; Robo4 knockdown by siRNA or Cre-mediated deletion causes severe defects in radial migration with neuronal misorientation, and sensitizes neurons to Slit repulsion, demonstrating Slit-dependent and -independent roles. In utero electroporation with siRNA/Cre, transwell migration assay, growth cone collapse assay, floxed Robo4 mice Cerebral cortex High 22123939
2006 Robo4 mediates attraction signaling in zebrafish vascular endothelial cells by activating Cdc42 and Rac1 Rho GTPases; robo4 knockdown in zebrafish results in reduced active Cdc42 and Rac1, with angioblasts showing impaired directional guidance. Gain-of-function Robo4 expression in endothelial cells, robo4 morpholino knockdown in zebrafish, Rho GTPase activity assays Journal of biological chemistry Medium 16481322
2010 Endothelial Robo4 restricts VEGF-R2 signaling through Src and FAK kinases to limit blood vessel growth in the mammary gland; loss of Robo4 (but not Robo1) in endothelium combined with an angiogenic stimulus phenocopies loss of stromal Slit, resulting in elevated vessel density. Conditional Robo4 and Robo1 knockout mouse models, genetic epistasis, VEGFR2/Src/FAK signaling analysis Proceedings of the National Academy of Sciences High 20498081
2013 Slit2-N/Robo4 signaling induces internalization of VEGFR-3 to block its activation, and inhibits PI3K/Akt pathway activation by VEGF-C in lymphatic endothelial cells, thereby suppressing lymphangiogenesis in a Robo4-dependent manner. siRNA Robo4 knockdown, VEGFR-3 internalization assay, PI3K/Akt activation assay, lymphatic endothelial cell migration/proliferation/tube formation assays Cell communication and signaling Medium 24708522
2013 Slit2/Robo4 signaling represses LPS-induced endothelial inflammation by inhibiting the Pyk2-NF-κB pathway downstream of LPS-TLR4; Robo4 is the dominant anti-inflammatory receptor while Robo1 is pro-inflammatory and is downregulated by Slit2 via miR-218. siRNA knockdown of Robo4/Robo1 in HUVECs, NF-κB/Pyk2 signaling analysis, cytokine/chemokine measurement, miR-218 analysis Journal of immunology Medium 24272999
2016 The cytoplasmic domain of Robo4 is dispensable for vascular permeability and neovascularization; truncated Robo4 lacking the cytoplasmic domain (Robo4ΔCD) is sufficient to prevent permeability and inhibit OIR revascularization. Robo4 (and Robo4ΔCD) counteract VEGFR2-Y949 phosphorylation by signaling through the endothelial UNC5B receptor, independently of Slit2 signaling. Transgenic mice expressing cytoplasmic-domain-truncated Robo4, oxygen-induced retinopathy model, wound healing model, VEGFR2 phosphorylation analysis Nature communications High 27882935
2018 Annexin A2 (ANXA2) acts as a Robo4 ligand; recombinant ANXA2 reduces trans-endothelial permeability by modulating signaling via the Robo4-paxillin-ARF6 pathway in brain endothelial cells, reducing ARF6 activity and maintaining endothelial tightness. ANXA2 knockout mice, recombinant ANXA2 treatment, Robo4-paxillin-ARF6 signaling analysis, TEER and tracer leakage assays Journal of cerebral blood flow and metabolism Medium 29786451
2019 Robo4 forms a complex with TRAF7 (TNF receptor-associated factor 7, a ubiquitin E3 ligase) via the C-terminus of Robo4; this Robo4-TRAF7 complex suppresses TNFα-induced endothelial hyperpermeability by stabilizing VE-cadherin at cell junctions. Co-IP/binding assays, deletion assays mapping C-terminus interaction, TRAF7 gain/loss-of-function, VE-cadherin localization assay, Robo4-/- endotoxemia mouse model Journal of cell science High 30510113
2018 ETV2 directly interacts with TET1 and TET2 methylcytosine-converting enzymes; ETV2-TET1/TET2 complexes demethylate the Robo4 proximal promoter to induce endothelial-specific Robo4 expression during differentiation from iPSCs to endothelial cells. Co-immunoprecipitation (ETV2-TET1/TET2 interaction), reporter assays, adenoviral ETV2-TET1/TET2 overexpression in non-ECs, bisulfite sequencing for promoter methylation Scientific reports Medium 29618782
2004 Soluble Robo4 extracellular domain (Robo4Fc) inhibits angiogenesis in vivo and endothelial migration/proliferation/tube formation in vitro; however, Slit1, Slit2, and Slit3 bind Robo1 but not Robo4 by immunoprecipitation and BiaCore analysis, suggesting Robo4 uses a different ligand mechanism. In vivo sponge angiogenesis model, rat aortic ring assay, VEGF/bFGF migration assay, immunoprecipitation, BiaCore binding analysis FASEB journal Medium 15486058
2015 ROBO4 signaling in endothelial cells suppresses breast cancer growth and metastasis by regulating tumor angiogenesis, endothelial leakage, and tight junction protein ZO-1 levels; pharmacological activation of ARF6 inhibition downstream of Robo4 (using SecinH3) mimics Robo4 activation and reduces tumor angiogenesis. Robo4 knockout immunocompetent mouse breast cancer model, tumor angiogenesis quantification, SecinH3 pharmacological treatment, ZO-1 expression analysis Molecular oncology Medium 26778715
2015 Vascular endothelial ROBO4 actively promotes HSC extravasation from blood into bone marrow (trans-endothelial migration), while simultaneously maintaining vascular barrier function to prevent BM-to-blood escape, thereby regulating directionality of HSC trafficking. ROBO4 knockout mice, induced vascular permeability experiments, HSC tracking/engraftment assays Stem cell reports Medium 25640759
2012 Robo4 knockdown in retinal endothelial cells increases permeability, reduces tight junction proteins ZO-1 and occludin, causes F-actin rearrangement, and activates the LIMK/cofilin pathway, revealing a signaling cascade mediating barrier function. siRNA knockdown, RITC-dextran permeability assay, Western blotting for TJ proteins and LIMK/cofilin, immunofluorescence for F-actin Current eye research Medium 23163536
2022 Soluble Robo4 is generated by constitutive ectodomain shedding by ADAM10 and ADAM17 (disintegrin metalloproteinases); Slit3 induces cell-surface Robo4 endocytosis, thereby shielding Robo4 from shedding by ADAMs and enhancing Robo4 signaling. Shed soluble Robo4 inhibits Slit3-induced angiogenesis. ADAM10/ADAM17 inhibitor and siRNA studies, Robo4 shedding assays, endocytosis assays with Slit3 treatment, angiogenesis functional assays Scientific reports Medium 35288626
2023 ALK5-SMAD2/3 and ALK1-SMAD1/5 signaling pathways positively and negatively regulate Robo4 expression, respectively; endothelial-specific Robo4 overexpression suppresses vascular permeability and reduces mortality in LPS-treated and SARS-CoV-2-infected mice. ALK1 inhibitor screening, SMAD pathway analysis, endothelial-specific Robo4 transgenic overexpression mice, LPS endotoxemia and SARS-CoV-2 infection models, vascular permeability assays Proceedings of the National Academy of Sciences High 36634143
2024 ROBO4 interacts with IQGAP1 and TRAF7; in this complex, ROBO4 enhances IQGAP1 ubiquitination through the E3 ligase TRAF7, inhibits prolonged RAC1 activation, and decreases PTGS2/COX-2 expression in inflammatory endothelial cells, thereby suppressing prostaglandin-mediated vascular inflammation. RNA-seq, Co-IP (ROBO4-IQGAP1-TRAF7 complex), ubiquitination assay, RAC1 activation assay, Robo4-/- mouse models of arthritis/edema/pain Communications biology High 38762541
2024 USP5 stabilizes ROBO4 protein through deubiquitination; USP5 overexpression increases ROBO4 levels and aggravates high-glucose-induced retinal pigment epithelial cell damage, while USP5 knockdown decreases ROBO4 and mitigates this damage. Co-immunoprecipitation, deubiquitination assay, USP5 and ROBO4 overexpression/knockdown, cell damage assays in high-glucose conditions Cellular signalling Medium 38735506
2017 Recombinant Slit2 reduces surgical brain injury-induced BBB disruption via Robo4 and paxillin; Robo4 and paxillin siRNA knockdown reverses Slit2-mediated Rac1 activation, placing Robo4 upstream of a paxillin-Rac1 signaling axis in BBB protection. Robo4 and paxillin siRNA knockdown, Rac1 activity assay, recombinant Slit2 treatment, BBB permeability assays in SBI rat model Scientific reports Medium 28389649
2018 ROBO4 variants (missense and rare) segregate with bicuspid aortic valve and thoracic aortic aneurysm; silencing ROBO4 or expressing mutant ROBO4 in endothelial cell lines impairs barrier function and induces a gene expression repertoire consistent with endothelial-to-mesenchymal transition. Targeted sequencing in families, siRNA knockdown and mutant ROBO4 expression in endothelial lines, barrier function assays, EMT gene expression profiling Nature genetics Medium 30455415
2019 Robo4 deletion in mice ameliorates platelet-activating factor (PAF)-mediated skin inflammation by reducing LPCAT1/LPCAT2 mRNA translation efficiency (via reduced ribosome and ATP levels), decreasing PAF receptor expression in macrophages, and suppressing LPS-induced IL-6 and p44/42/p65 phosphorylation while enhancing AKT phosphorylation. Robo4 KO mouse model, polyribosome assay for LPCAT1/LPCAT2 mRNA, HPLC for ATP, Western blot for signaling proteins, immunohistochemistry International journal of biological sciences Medium 32140075
2024 Robo4 depletion in bone marrow endothelial cells promotes endothelial-to-mesenchymal transition (EndMT) by increasing endoglin (CD105) expression and activating both canonical (Smad) and non-canonical (AKT/NF-κB) TGF-β signaling, leading to Snail1 nuclear translocation; Robo4 overexpression stimulates ICAM-1 and VCAM-1 expression and suppresses EndMT and irradiation-induced permeability. Lentiviral RNAi and overexpression in endothelial cells, γ-radiation injury model, Western blot for Smad/AKT/NF-κB/Snail1, co-culture with HSPCs Cell death & disease Medium 38383474
2021 HDAC3 (but not HDAC1 or HDAC2) maintains Robo4 expression in endothelial cells by sustaining GABP transcription factor expression; HDAC3-specific siRNA knockdown or the HDAC inhibitor MS-275 reduces GABP and Robo4 promoter activity, increases endothelial permeability, and enhances vascular leakage in mouse lungs. HDAC isoform-specific siRNA, HDAC inhibitor MS-275, Robo4 promoter reporter assay, TEER assay, Evans blue leakage in vivo Tissue barriers Medium 33955828
2021 Acute endothelial-specific deletion of Robo4 impairs HSC distribution between bone marrow and blood, perturbs long-term donor HSC engraftment, and improves HSC mobilization, independently of VCAM1 expression on sinusoidal vascular endothelial cells. Conditional Robo4 deletion mouse models, HSC trafficking/engraftment assays, VCAM1 protein level analysis on sinusoidal VECs PloS one Medium 34388149
2013 SLIT3 secreted by pericytic mesenchymal stem cells guides vascular network formation via ROBO4-positive endothelial cells; siRNA knockdown of SLIT3 in MSCs leads to disorganized EC clustering, and ROBO4 knockdown in ECs abolishes functional human blood vessel generation in vivo in a xenograft model. siRNA knockdown of SLIT3 (in MSCs) and ROBO4 (in ECs), 3D vascular network live imaging, in vivo xenogenic implant model Journal of molecular and cellular cardiology Medium 24090675

Source papers

Stage 0 corpus · 90 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. Nature medicine 320 18345009
2010 Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Science translational medicine 280 20375003
2003 Robo4 is a vascular-specific receptor that inhibits endothelial migration. Developmental biology 269 12941633
2009 Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity. Nature cell biology 194 19855388
2011 Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B. Developmental cell 174 21238923
2004 Soluble Robo4 receptor inhibits in vivo angiogenesis and endothelial cell migration. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 146 15486058
2018 ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. Nature genetics 117 30455415
2011 Robo4 cooperates with CXCR4 to specify hematopoietic stem cell localization to bone marrow niches. Cell stem cell 107 21211783
2008 Active involvement of Robo1 and Robo4 in filopodia formation and endothelial cell motility mediated via WASP and other actin nucleation-promoting factors. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 100 18948384
1972 Cell wall peptidoglycan mutants of Escherichia coli K-12: existence of two clusters of genes, mra and mrb, for cell wall peptidoglycan biosynthesis. Journal of bacteriology 81 4563986
2013 Slit2-Robo4 pathway modulates lipopolysaccharide-induced endothelial inflammation and its expression is dysregulated during endotoxemia. Journal of immunology (Baltimore, Md. : 1950) 80 24272999
2006 Robo4 signaling in endothelial cells implies attraction guidance mechanisms. The Journal of biological chemistry 71 16481322
2010 Vascular Robo4 restricts proangiogenic VEGF signaling in breast. Proceedings of the National Academy of Sciences of the United States of America 70 20498081
2006 Robo1/Robo4: differential expression of angiogenic markers in colorectal cancer. Oncology reports 66 16685377
2007 A three-kilobase fragment of the human Robo4 promoter directs cell type-specific expression in endothelium. Circulation research 64 17495228
2013 SLIT3-ROBO4 activation promotes vascular network formation in human engineered tissue and angiogenesis in vivo. Journal of molecular and cellular cardiology 53 24090675
2020 Esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker (MRB) in hypertension and chronic kidney disease. Journal of human hypertension 48 32661269
2016 The Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization. Nature communications 47 27882935
2015 ROBO4-mediated vascular integrity regulates the directionality of hematopoietic stem cell trafficking. Stem cell reports 43 25640759
2011 Robo4 regulates the radial migration of newborn neurons in developing neocortex. Cerebral cortex (New York, N.Y. : 1991) 39 22123939
2019 Enhanced ROBO4 is mediated by up-regulation of HIF-1α/SP1 or reduction in miR-125b-5p/miR-146a-5p in diabetic retinopathy. Journal of cellular and molecular medicine 38 31094072
2019 Regulatory mechanisms of Robo4 and their effects on angiogenesis. Bioscience reports 38 31160487
2011 Robo4-dependent Slit signaling stabilizes the vasculature during pathologic angiogenesis and cytokine storm. Current opinion in hematology 38 21423011
2015 Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis. Molecular oncology 37 26778715
2008 A GABP-binding element in the Robo4 promoter is necessary for endothelial expression in vivo. Blood 36 18519813
2014 Role of ROBO4 signalling in developmental and pathological angiogenesis. BioMed research international 32 24689049
2018 Annexin A2 is a Robo4 ligand that modulates ARF6 activation-associated cerebral trans-endothelial permeability. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 31 29786451
2014 Slit2N and Robo4 regulate lymphangiogenesis through the VEGF-C/VEGFR-3 pathway. Cell communication and signaling : CCS 31 24708522
2012 Slit2/Robo4 signaling modulates HIV-1 gp120-induced lymphatic hyperpermeability. PLoS pathogens 31 22241990
2010 MR angiogenesis imaging with Robo4- vs. alphaVbeta3-targeted nanoparticles in a B16/F10 mouse melanoma model. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 29 20585027
2009 Expression of Robo4 in the fibrovascular membranes from patients with proliferative diabetic retinopathy and its role in RF/6A and RPE cells. Molecular vision 29 19495426
2019 The Robo4-TRAF7 complex suppresses endothelial hyperpermeability in inflammation. Journal of cell science 27 30510113
2018 ETV2-TET1/TET2 Complexes Induce Endothelial Cell-Specific Robo4 Expression via Promoter Demethylation. Scientific reports 26 29618782
2013 Robo4 is an effective tumor endothelial marker for antibody-drug conjugates based on the rapid isolation of the anti-Robo4 cell-internalizing antibody. Blood 26 23365463
2017 Enhanced VEGF signalling mediates cerebral neovascularisation via downregulation of guidance protein ROBO4 in a rat model of diabetes. Diabetologia 25 28116460
2018 Slit2/Robo4 axis may contribute to endothelial cell dysfunction and angiogenesis disturbance in systemic sclerosis. Annals of the rheumatic diseases 24 30021803
2017 Endothelial Robo4 regulates IL-6 production by endothelial cells and monocytes via a crosstalk mechanism in inflammation. Biochemical and biophysical research communications 24 29137978
2017 Recombinant Slit2 Reduces Surgical Brain Injury Induced Blood Brain Barrier Disruption via Robo4 Dependent Rac1 Activation in a Rodent Model. Scientific reports 21 28389649
2015 Suppression of Slit2/Robo1 mediated HUVEC migration by Robo4. Biochemical and biophysical research communications 21 26713366
2013 Slit2-Robo4 receptor responses inhibit ANDV directed permeability of human lung microvascular endothelial cells. Antiviral research 19 23702092
2019 Upregulated VEGF and Robo4 correlate with the reduction of miR-15a in the development of diabetic retinopathy. Endocrine 18 30980286
2014 Robo4 vaccines induce antibodies that retard tumor growth. Angiogenesis 18 25348086
2008 Robo1/robo4: different expression patterns in retinal development. Experimental eye research 18 19084519
2023 OncoTherad® (MRB-CFI-1) Nanoimmunotherapy: A Promising Strategy to Treat Bacillus Calmette-Guérin-Unresponsive Non-Muscle-Invasive Bladder Cancer: Crosstalk among T-Cell CX3CR1, Immune Checkpoints, and the Toll-Like Receptor 4 Signaling Pathway. International journal of molecular sciences 17 38139364
2023 Upregulation of Robo4 expression by SMAD signaling suppresses vascular permeability and mortality in endotoxemia and COVID-19 models. Proceedings of the National Academy of Sciences of the United States of America 16 36634143
2021 HDAC inhibitor, MS-275, increases vascular permeability by suppressing Robo4 expression in endothelial cells. Tissue barriers 16 33955828
2024 Endothelial ROBO4 suppresses PTGS2/COX-2 expression and inflammatory diseases. Communications biology 14 38762541
2021 Salidroside Prevents Hypoxia-Induced Human Retinal Microvascular Endothelial Cell Damage Via miR-138/ROBO4 Axis. Investigative ophthalmology & visual science 12 34269814
2016 Increased expression of Slit2 and its receptors Robo1 and Robo4 in reactive astrocytes of the rat hippocampus after transient forebrain ischemia. Brain research 12 26764532
2012 Robo4 plays a role in bone marrow homing and mobilization, but is not essential in the long-term repopulating capacity of hematopoietic stem cells. PloS one 12 23226403
2014 Raised plasma Robo4 and cardiac surgery-associated acute kidney injury. PloS one 11 25360813
2009 Functionally defining the endothelial transcriptome, from Robo4 to ECSCR. Biochemical Society transactions 11 19909249
2023 The role of TET2-mediated ROBO4 hypomethylation in the development of diabetic retinopathy. Journal of translational medicine 10 37430272
2022 OncoTherad® (MRB-CFI-1) nano-immunotherapy reduced tumoral progression in non-muscle invasive bladder cancer through activation of Toll-like signaling pathway. Tissue & cell 10 35245856
2022 Robo4 is constitutively shed by ADAMs from endothelial cells and the shed Robo4 functions to inhibit Slit3-induced angiogenesis. Scientific reports 10 35288626
2019 MicroRNA-411 plays a protective role in diabetic retinopathy through targeted regulating Robo4. European review for medical and pharmacological sciences 10 31773667
2012 Effect of Robo4 on retinal endothelial permeability. Current eye research 10 23163536
2024 The Role of SLIT3-ROBO4 Signaling in Endoplasmic Reticulum Stress-Induced Delayed Corneal Epithelial and Nerve Regeneration. Investigative ophthalmology & visual science 9 38700874
2023 Robo4 inhibits gamma radiation-induced permeability of a murine microvascular endothelial cell by regulating the junctions. Cellular & molecular biology letters 9 36647012
2019 miR-204 Negatively Regulates Cell Growth And Metastasis By Targeting ROBO4 In Human Bladder Cancer. OncoTargets and therapy 9 31802889
2018 Slit2/Robo4 signaling pathway modulates endothelial hyper-permeability in a two-event in vitro model of transfusion-related acute lung injury. Blood cells, molecules & diseases 9 30846360
2015 Expression of the Robo4 receptor in endothelial cells is regulated by two AP-1 protein complexes. Biochemical and biophysical research communications 9 26459591
2021 Aminophylline modulates the permeability of endothelial cells via the Slit2-Robo4 pathway in lipopolysaccharide-induced inflammation. Experimental and therapeutic medicine 8 34373728
2021 Acute and endothelial-specific Robo4 deletion affect hematopoietic stem cell trafficking independent of VCAM1. PloS one 7 34388149
2017 Slit2/Robo4 Signaling: Potential Role of a VEGF-Antagonist Pathway to Regulate Luteal Permeability. Geburtshilfe und Frauenheilkunde 7 28190892
2024 Endothelial Robo4 suppresses endothelial-to-mesenchymal transition induced by irradiation and improves hematopoietic reconstitution. Cell death & disease 6 38383474
2024 USP5 facilitates diabetic retinopathy development by stabilizing ROBO4 via deubiquitination. Cellular signalling 5 38735506
2022 Mechanism of TLR4 mediated immune effect in transfusion-induced acute lung injury based on Slit2/Robo4 signaling pathway. Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis 5 35853810
2020 ROBO4 deletion ameliorates PAF-mediated skin inflammation via regulating the mRNA translation efficiency of LPCAT1/LPCAT2 and the expression of PAF receptor. International journal of biological sciences 5 32140075
2019 Deletion of Robo4 prevents high-fat diet-induced adipose artery and systemic metabolic dysfunction. Microcirculation (New York, N.Y. : 1994) 5 30825241
2022 BML-111 alleviates inflammatory response of alveolar epithelial cells via miR-494/Slit2/Robo4 signalling axis to improve acute lung injury. Autoimmunity 4 35656971
2020 DS-7080a, a Selective Anti-ROBO4 Antibody, Shows Anti-Angiogenic Efficacy with Distinctly Different Profiles from Anti-VEGF Agents. Translational vision science & technology 4 32879763
2019 Inhibitory Effect of Slit2-N on VEGF165-induced proliferation of vascular endothelia via Slit2-N-Robo4-Akt pathway in choroidal neovascularization. Cell cycle (Georgetown, Tex.) 4 31081721
2019 Robo4 contributes to the turnover of Peyer's patch B cells. Mucosal immunology 4 31772321
2019 Expression of HIF-1α and Robo4 in the retinas of streptozotocin-induced diabetic mice. International journal of clinical and experimental pathology 4 31933855
2012 [Transcriptional regulation of the endothelial cell-specific receptor, Robo4]. Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 4 23023422
2024 Slit2-Robo4 signal pathway and tight junction in intestine mediate LPS-induced inflammation in mice. European journal of medical research 3 38937814
2024 Modulation of the tumor microenvironment in non-muscle-invasive bladder cancer by OncoTherad® (MRB-CFI-1) nanoimmunotherapy: effects on tumor-associated macrophages, tumor-infiltrating lymphocytes, and monoamine oxidases. Medical oncology (Northwood, London, England) 3 39404781
2020 PRC2 Components Maintain DNA Hypermethylation of the Upstream Promoter and Regulate Robo4 Expression in Endothelial Cells. Biological & pharmaceutical bulletin 3 32238717
2013 [Myocardial Slit2/Robo4 expression and impact of exogenous Slit2 on proliferation and migration of cardiac microvascular endothelial cells]. Zhonghua xin xue guan bing za zhi 3 24524607
2008 Ligand-independent assembly of purified soluble magic roundabout (Robo4), a tumor-specific endothelial marker. Protein expression and purification 3 18571431
2025 Clinical and immunohistochemical effects of OncoTherad (MRB-CFI-1) nanoimmunotherapy on SERBP1, HABP4, CD44 and Ki-67 in BCG-unresponsive non-muscle invasive bladder cancer. Tissue & cell 1 39938427
2024 A novel serous ovarian carcinoma model induced by DMBA: Results from OncoTherad® (MRB-CFI-1) immunotherapy preclinical testing. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 1 39693910
2022 Binding and Efficacy of Anti-Robo4 CAR-T Cells against Solid Tumors. Biomedicines 1 35740295
2020 Withdrawal Notice: Molecular Mechanism of TLR4 Mediated T Cell Immune Effect in Transfusion-induced Acute Lung Injury based on Slit2/Robo4 Signaling Pathway. Current molecular pharmacology 1 33030140
2026 Congenital Coarctation of the Aorta in a Patient With ROBO4 c.695C>T (p.Thr232Met) Germline Variant. Annals of internal medicine. Clinical cases 0 41613935
2026 Leveraging in-silico deep learning and computational analyses to predict the pathogenicity of ROBO4 variants of uncertain significance in aortic aneurysm and dissection patients. BMC cardiovascular disorders 0 41639767
2025 Robo4 inhibits neovascularization in oxygen-induced retinopathy by regulating ARF6 and VEGF. Human cell 0 40778968
2024 A great diversity of ROBO4 expression and regulations identified by data mining and transgene mice. Gene expression patterns : GEP 0 39181524
2022 [The destructive role of soluble Robo4 secreted by the M1-polarized-microglia during cerebral ischemia-reperfusion in blood-brain barrier integrity]. Sheng li xue bao : [Acta physiologica Sinica] 0 35993202