Affinage

ROBO1

Roundabout homolog 1 · UniProt Q9Y6N7

Length
1651 aa
Mass
180.9 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ROBO1 is a transmembrane immunoglobulin superfamily receptor that transduces Slit ligand signals to regulate axon guidance, cell migration, branching morphogenesis, and tumor suppression across diverse tissues. Upon Slit2 binding—facilitated by heparan sulfate proteoglycans engaging two distinct sites on the ectodomain—ROBO1 signals through srGAP1-mediated Cdc42/RhoA inhibition, Rac1 modulation via DOCK1 and CdGAP, and PI3K/Akt-dependent sequestration of β-catenin from the nucleus, thereby restraining Wnt-driven proliferation and controlling cytoskeletal dynamics (PMID:22826604, PMID:27923383, PMID:24752651, PMID:25752613). Surface expression of ROBO1 is tightly regulated by RabGDI-dependent vesicle trafficking, miR-92-mediated translational repression, NOVA-regulated alternative splicing of a conserved microexon, and NEDD4-mediated ubiquitin-proteasomal degradation recruited by PRRG4, while the ectodomain undergoes sequential metalloproteinase and γ-secretase cleavage to release an intracellular fragment that translocates to the nucleus (PMID:23140504, PMID:30184503, PMID:31392959, PMID:33037408, PMID:20471383). ROBO1 functions as a two-hit tumor suppressor—heterozygous knockout mice develop lymphomas and lung adenocarcinomas with epigenetic silencing of the remaining allele—while in other contexts SLIT2/ROBO1 signaling promotes angiogenesis and cancer cell migration through SRC/ERK and FAK pathways (PMID:15374951, PMID:25894826, PMID:26975850).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    Establishing that Robo1 is required for normal organ development: targeted deletion of the first Ig domain in mice revealed delayed lung maturation and bronchial hyperplasia, demonstrating a developmental role beyond axon guidance.

    Evidence Germline knockout mouse with histopathology

    PMID:11734623

    Open questions at the time
    • Mechanism by which Robo1 controls epithelial maturation undefined
    • Ligand dependency not tested
  2. 2002 High

    Demonstrating that ROBO1 acts as a tumor suppressor silenced by epigenetic mechanisms: promoter hypermethylation was found in breast and renal cancers, and demethylation reactivated expression, establishing a two-hit inactivation model later confirmed by heterozygous mice developing spontaneous tumors.

    Evidence Bisulfite sequencing, pharmacologic demethylation, LOH analysis in human tumors; heterozygous KO mice developing lymphomas and adenocarcinomas with second-hit methylation

    PMID:12082532 PMID:15374951

    Open questions at the time
    • Tumor suppressor mechanism at signaling level not elucidated at this stage
    • Tissue-specificity of tumor spectrum unexplained
  3. 2006 High

    Defining ROBO1's in vivo role in forebrain axon guidance and interneuron migration: knockout mice showed corpus callosum dysgenesis and increased cortical interneuron migration, confirming Slit/Robo-mediated repulsion governs midline crossing decisions in the mammalian brain.

    Evidence Targeted knockout mouse with MRI DTI, immunohistochemistry, and axon tracing

    PMID:16690755

    Open questions at the time
    • Relative contributions of Robo1 vs Robo2 at the midline not fully resolved
    • Downstream signaling effectors in these neurons not identified
  4. 2010 High

    Revealing regulated intramembrane proteolysis of ROBO1: sequential metalloproteinase and γ-secretase cleavage generates an intracellular fragment that accumulates in the nucleus, suggesting a signaling mechanism analogous to Notch; crystal structure of the juxtamembrane domain later showed how the JM linker conformation regulates ectodomain shedding.

    Evidence Pharmacological inhibitors, subcellular fractionation, mass spectrometry of cleavage sites; X-ray crystallography of JM domain with shedding assay

    PMID:20471383 PMID:24607414

    Open questions at the time
    • Nuclear targets or transcriptional function of the intracellular fragment unknown
    • Physiological contexts triggering cleavage not defined
  5. 2010 High

    Identifying miR-218 as a direct negative regulator of ROBO1 mRNA: miR-218 targets the 3′UTR to suppress ROBO1 expression, and loss of miR-218 in cancer derepresses ROBO1 to promote invasion, establishing a regulatory feedback loop in the SLIT-ROBO pathway.

    Evidence Luciferase 3′UTR reporter assay, miR-218-resistant ROBO1 rescue, in vitro migration and in vivo xenograft

    PMID:20300657 PMID:21385904

    Open questions at the time
    • Whether miR-218 regulation is operative in normal developmental contexts not shown
    • Context dependency—ROBO1 acts as tumor suppressor vs oncogene—not reconciled
  6. 2011 High

    Connecting SLIT2/ROBO1 signaling to Wnt/β-catenin pathway inhibition in mammary epithelium: SLIT2 acting through ROBO1 restrains basal cell proliferation by redistributing β-catenin from nucleus to membrane, linking guidance cue signaling to a major proliferative pathway in branching morphogenesis.

    Evidence Conditional knockout in mammary gland, immunostaining, Western blot for β-catenin localization

    PMID:21664580

    Open questions at the time
    • Direct biochemical mechanism linking ROBO1 to β-catenin redistribution not resolved
    • Whether PI3K/Akt mediates the effect was addressed later but not in this study
  7. 2012 High

    Identifying downstream GTPase effectors: ROBO1 interacts with DOCK1 to control Rac1 activation, and separately with srGAP1 to inhibit Cdc42, establishing the receptor's cytoskeletal signaling arms; RabGDI was shown to control ROBO1 surface delivery on commissural axons.

    Evidence Co-IP with domain-specific mutants (DOCK1), reciprocal Co-IP with GTPase pull-down (srGAP1/Cdc42), in ovo RNAi and gain-of-function (RabGDI in chick)

    PMID:23140504 PMID:24752651 PMID:27923383

    Open questions at the time
    • How RabGDI specifically selects ROBO1-containing vesicles unknown
    • Whether DOCK1 and srGAP1 act in the same or distinct signaling complexes not tested
  8. 2013 High

    Characterizing the heparan sulfate co-receptor requirement: SPR and hydroxyl radical footprinting defined two separate HS binding sites on the ROBO1 ectodomain, with N-sulfo and 6-O-sulfo groups essential for binding; NMR later mapped the Ig1-2 binding epitope at residue-level resolution.

    Evidence SPR with modified heparin series, hydroxyl radical footprinting, site-directed mutagenesis, NMR chemical shift perturbation

    PMID:23994753 PMID:25752613 PMID:27653286

    Open questions at the time
    • Functional consequence of each HS binding site on Slit2 signaling output not separately tested in cells
    • Structural basis for ternary Slit2-HS-Robo1 complex not determined
  9. 2014 High

    Discovering FLRT3 as a co-receptor that converts ROBO1 from a repulsive to an attractive receptor: in the presence of Slit1, ROBO1-FLRT3 interaction upregulates surface DCC via PKA activation to enable Netrin-1 attraction, revealing context-dependent switching of guidance output.

    Evidence Co-IP, in vivo thalamic axon guidance in mouse, PKA activation and surface DCC assays

    PMID:24560577

    Open questions at the time
    • Whether FLRT3-ROBO1 complex forms in non-neuronal tissues unknown
    • Structural basis of the ROBO1-FLRT3 interaction not determined
  10. 2015 High

    Expanding ROBO1 function to angiogenesis, liver fibrosis, stem cell self-renewal, and immune cell regulation: Slit2/Robo1 drives retinal neovascularization via Rac1 and lamellipodia, activates hepatic stellate cells through Smad/PI3K/AKT phosphorylation, and controls mammary stem cell symmetric vs asymmetric division through SNAI1/mINSC.

    Evidence Conditional KO mice for retinal angiogenesis; neutralizing antibody and siRNA in HSCs; conditional KO with spindle orientation assays in mammary stem cells

    PMID:25894826 PMID:26264936 PMID:26440891

    Open questions at the time
    • How ROBO1 activates Smad2/3 independently of TGF-β remains mechanistically unclear
    • Whether stem cell division control is Slit-dependent or ligand-independent not distinguished
  11. 2016 High

    Defining ROBO1's mechanosensory function: SLIT2/ROBO1 signaling links ECM stiffness to cytoskeletal contractility via Rac and FAK activation, with stiff ECM upregulating ROBO1 by suppressing miR-203; Dscam1 was identified as a modulator that converts Robo1 repulsion into longitudinal growth in Drosophila.

    Evidence Robo1 ablation with ECM stiffness manipulation, Rac/FAK assays, miR-203 modulation; Dscam1-Robo1 Co-IP and genetic epistasis in Drosophila

    PMID:26975850 PMID:27654876

    Open questions at the time
    • Direct mechanosensory mechanism by which ECM stiffness controls miR-203 unknown
    • Whether Dscam1-Robo1 interaction is conserved in mammals not tested
  12. 2018 High

    Resolving the oligomeric architecture: crystal structure and EM reconstruction showed ROBO1 forms a dimer-of-dimers (tetramer) through central Ig domains, and Slit2-N binding induces conformational change rather than further oligomerization; miR-92 was identified as a translational repressor controlling timing of Robo1 responsiveness in commissural axons.

    Evidence X-ray crystallography of Ig1-4/Ig5, negative-stain EM, SAXS, fluorescent oligomerization imaging; 3′UTR reporter assay and in vivo chick commissural axon guidance for miR-92

    PMID:29307485 PMID:30184503

    Open questions at the time
    • Structural details of conformational change upon Slit2 binding not resolved at high resolution
    • Whether tetramerization is required for signaling not functionally tested
  13. 2019 High

    Revealing isoform-specific guidance activity through alternative splicing: NOVA splicing factors regulate inclusion of a conserved ROBO1 microexon, producing isoforms with distinct repulsive activities that temporally gate midline crossing decisions.

    Evidence NOVA genetics, isoform-specific rescue experiments in mouse commissural neurons

    PMID:31392959

    Open questions at the time
    • Structural basis for different signaling activities of splice isoforms unknown
    • Whether splicing regulation operates in non-neuronal ROBO1 functions not tested
  14. 2020 High

    Identifying NEDD4-mediated degradation as a post-translational control mechanism: PRRG4 recruits E3 ligase NEDD4 to ubiquitinate and degrade ROBO1, activating Src/FAK to promote breast cancer metastasis; separately, SLIT2/ROBO1 was shown to inhibit macropinocytosis and NOD2/NF-κB signaling in macrophages.

    Evidence Co-IP with motif mutants, ubiquitination assay, in vivo metastasis model; macropinocytosis assay with ROBO1 blocking, in vivo MDP uptake

    PMID:32807784 PMID:33037408

    Open questions at the time
    • Whether NEDD4-mediated degradation occurs in normal developmental contexts not shown
    • Mechanism by which ROBO1 inhibits macropinocytosis at the cytoskeletal level not fully defined
  15. 2024 High

    Establishing a PTP4A2-ROBO1 dephosphorylation axis in recurrent glioblastoma: genome-wide CRISPR screens revealed functional dependency on ROBO1 signaling, and ROBO1-targeted CAR T cells doubled median survival in xenograft models, validating ROBO1 as a therapeutic target.

    Evidence Genome-wide CRISPR screens, small-molecule PTP4A2 inhibition, ROBO1 CAR T cells in CDX models

    PMID:39095594

    Open questions at the time
    • Specific phosphorylation sites on ROBO1 targeted by PTP4A2 not mapped
    • ROBO1 CAR T efficacy in immunocompetent or patient-derived models not yet demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the nuclear function of the γ-secretase-released ROBO1 intracellular fragment; the structural basis of the Slit2-induced conformational change within the ROBO1 tetramer; how the tumor-suppressive and pro-migratory/pro-angiogenic activities of ROBO1 are contextually balanced; and whether the ROBO1 splice isoforms differentially engage non-neuronal signaling pathways.
  • Nuclear targets of ROBO1 ICD unidentified
  • Full-length Slit2-Robo1-HS ternary complex structure not determined
  • Context-dependent switching between tumor suppression and promotion mechanistically unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 6 R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 1
Partners
ARHGAP31DOCK1DSCAM1FLRT3NEDD4PTP4A2SLIT2SRGAP1
Complex memberships
Robo1 dimer-of-dimers (tetramer)Slit2-Robo1 receptor complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Targeted deletion of the first Ig domain of Dutt1/Robo1 in mice causes delayed lung maturation and bronchial epithelial hyperplasia, establishing Robo1 as required for normal lung development. Germline knockout mouse (targeted deletion of exon 2/first Ig domain), histopathology Proceedings of the National Academy of Sciences of the United States of America High 11734623
2002 Promoter hypermethylation of ROBO1/DUTT1 silences its expression in breast and renal cell carcinoma, and 5-aza-2'-deoxycytidine treatment reactivates expression, supporting epigenetic inactivation as a two-hit tumor suppressor mechanism. Bisulfite sequencing, methylation-specific analysis, 5-aza-2'-deoxycytidine demethylation, RT-PCR, LOH analysis Oncogene High 12082532
2004 Robo1 heterozygous mice spontaneously develop lymphomas and lung adenocarcinomas, with promoter methylation silencing the remaining wild-type allele in tumors, confirming Robo1 as a classic two-hit tumor suppressor. Heterozygous knockout mouse, LOH analysis, methylation analysis, Western blot, immunohistochemistry Cancer research High 15374951
2006 Robo1 knockout mice display axon pathfinding defects (corpus callosum and hippocampal commissure dysgenesis, premature corticothalamic/thalamocortical targeting) and increased cortical interneuron migration, demonstrating Robo1's role in forebrain axon guidance and interneuron migration in vivo. Targeted knockout mouse, MRI diffusion tensor imaging, immunohistochemistry, axon tracing Development (Cambridge, England) High 16690755
2010 ROBO1 ectodomain is shed by metalloproteinases, followed by gamma-secretase cleavage producing two C-terminal fragments (CTF1 at 129 kDa, CTF2 at 118 kDa), and the resulting intracellular fragment accumulates in the nucleus in cancer cells; this nuclear translocation is blocked by metalloproteinase or gamma-secretase inhibitors. Pharmacological inhibition (TAPI-1, L-685,458), Western blot, cellular fractionation, mass spectrometry of cleavage sites FEBS letters High 20471383
2010 Decreased miR-218 levels eliminate repression of Robo1, activating the Slit2-Robo1 pathway (via Slit2-Robo1 interaction) to promote gastric cancer metastasis; restoration of miR-218 suppresses Robo1 expression and inhibits tumor cell invasion in vitro and in vivo. miRNA overexpression/restoration, in vitro invasion assay, in vivo xenograft, luciferase 3'UTR reporter assay PLoS genetics High 20300657
2010 miR-218 directly targets the 3'UTR of ROBO1 mRNA to suppress its expression; enforced expression of miR-218-resistant ROBO1 rescues NPC cell migration, establishing a negative feedback loop wherein miR-218 regulates cell migration via the SLIT-ROBO1 pathway. Luciferase 3'UTR reporter assay, rescue with miR-218-resistant ROBO1 isoform, migration assays, in vivo tumor growth Cancer research High 21385904
2010 Robo1 mediates Slit2-induced repulsive effects on glioma cell migration; RNAi-mediated knockdown of Robo1 neutralizes Slit2's repulsive effect in a modified Boyden chamber assay, demonstrating Robo1 as the principal Slit2 receptor in glioma cells. RNAi knockdown, modified Boyden chamber migration assay, qRT-PCR, immunohistochemistry Journal of neuro-oncology Medium 17968499
2011 SLIT2/ROBO1 signaling restrains mammary branching morphogenesis by limiting basal cell proliferation; TGF-β1 induces Robo1 expression specifically in the basal layer, and SLIT2 limits basal cell proliferation by inhibiting canonical WNT signaling, increasing cytoplasmic/membrane β-catenin at the expense of nuclear β-catenin. Conditional knockout (basal layer-specific loss of SLIT/ROBO1 signaling), immunostaining, Western blot, mammary gland whole-mount analysis Developmental cell High 21664580
2012 Slit2 secreted by stromal fibroblasts activates Robo1 in breast cancer cells to block β-catenin nuclear translocation, downregulating c-myc and cyclin D1 via the PI3K/Akt pathway, thereby restraining breast cancer tumorigenesis. Co-culture, Robo1 overexpression/knockdown, PI3K/Akt pathway inhibitors, β-catenin localization assays, in vivo xenograft Cancer research High 22826604
2012 RabGDI, an essential component of vesicle fusion machinery, regulates Robo1 surface expression on commissural axons in vertebrates; downregulation of RabGDI causes axons to stall in the floor plate (phenocopying Robo1 loss), while premature RabGDI expression prevents floor plate entry, and RabGDI directly triggers Robo1 surface expression in cultured commissural neurons. In ovo RNAi, immunofluorescence, cultured commissural neuron assay, gain-of-function and loss-of-function genetics (chick) Neural development High 23140504
2012 ROBO1 interaction with DOCK1 (at SH3-SH2 domain) controls Rac activation; loss of ROBO1 results in Rac1 activation, causing E-cadherin/β-catenin cytoskeleton destabilization and induction of cell migration in prostate cancer cells. ROBO1-expressing/ROBO1-C2C3-mutant constructs, immunoprecipitation, confocal microscopy, luciferase reporter, migration assays International journal of cancer Medium 24752651
2013 srGAP1 is a Robo1-interacting protein; Slit2-Robo1 signaling inhibits Cdc42 activity and colorectal cancer cell motility through srGAP1, as shown by co-immunoprecipitation and subcellular co-localization after Slit2 treatment. Immunoprecipitation, immunofluorescence, small GTPase pull-down assay, modified wound healing assay Journal of experimental & clinical cancer research High 27923383
2013 Heparin binds to Robo1 with ~650 nM affinity; N-sulfo and 6-O-sulfo groups are essential for Robo1-heparin binding; Robo1 prefers full-length heparin chains, and GAGs with higher sulfation show increased Robo1 binding affinity. Surface plasmon resonance (SPR), chemically modified heparin competition assay, heparin oligosaccharide size-series binding Biochimie High 23994753
2014 FLRT3 is a novel co-receptor for Robo1; in the presence of Slit1, both Robo1 and FLRT3 are required to induce Netrin-1 attraction via upregulation of surface DCC through activation of protein kinase A, revealing a context-dependent modulation of guidance cue responses. Co-immunoprecipitation, axon guidance assays in vitro and in vivo (thalamic axon guidance in mouse), surface DCC measurement, PKA activation assay Current biology : CB High 24560577
2014 The crystal structure of the extracellular juxtamembrane (JM) domains of human Robo1 reveals structural similarity to neogenin/DCC netrin-binding regions; a conserved surface overlapping oncogenic mutations is identified, and exposure or relief of the folded JM linker enhances ectodomain shedding of Robo1 in cultured cells. X-ray crystallography, structural comparison, cell-based ectodomain shedding assay Journal of structural biology High 24607414
2015 Two separate heparin binding sites on Robo1 were identified by hydroxyl radical protein footprinting: one at the previously characterized site and a second N-terminal site (disordered in crystal structure); mutagenesis of the N-terminal site decreases heparin binding affinity, and heparin binding induces conformational changes in the Ig2 domain. Electron transfer dissociation-based hydroxyl radical protein footprinting, site-directed mutagenesis, SPR, heparin affinity chromatography The Journal of biological chemistry High 25752613
2015 Slit2 signaling through Robo1 and Robo2 promotes retinal neovascularization by driving endothelial cell migration; Robo1/2 are required for both Slit2- and VEGF-induced Rac1 activation and lamellipodia formation in endothelial cells. Conditional knockout mice (Slit2, Robo1, Robo2), retinal angiogenesis assays, Rac1 activation assay, lamellipodia formation assay, endothelial cell migration assay Nature medicine High 25894826
2015 Slit2-Robo1 signaling activates hepatic stellate cells (HSCs) to promote liver fibrosis through phosphorylation of Smad2, Smad3, PI3K, and AKT in an TGF-β1-independent manner; Robo1 neutralizing antibody R5 and Robo1 siRNA downregulate these phosphorylation events and inhibit α-SMA expression. Robo1 neutralizing antibody, Robo1 siRNA, Western blot (pSmad2/3, PI3K, AKT), primary mouse and human HSC cultures, Slit2 transgenic mice, Robo1/2 heterozygous knockout mice, CCl4 liver injury model Journal of hepatology High 26264936
2015 SLIT2/ROBO1 signaling regulates mammary stem cell self-renewal by controlling the choice between asymmetric and symmetric cell divisions through SNAI1 and mINSC; loss of SLIT2/ROBO1 signaling increases nuclear SNAI1, which upregulates mInsc and increases symmetric cell divisions, producing more stem cells and larger mammary outgrowths. Conditional knockout, in vivo mammary transplantation, SNAI1 overexpression/knockdown, mInsc expression analysis, spindle orientation assays Cell reports High 26440891
2015 Robo2 acts in trans to inhibit Slit-Robo1 repulsion and promote midline crossing in Drosophila; Robo2 binds Robo1 via extracellular domains, and this binding is required for Robo2's ability to promote crossing non-cell autonomously. Gain-of-function and rescue genetics in Drosophila, extracellular domain binding studies, non-cell-autonomous overexpression assays eLife High 26186094
2015 Recombinant Slit2 reduces peripheral immune cell infiltration after surgical brain injury via the Robo1-srGAP1 pathway, mediating inhibition of Cdc42 activity; decoy Robo1 and srGAP1 siRNA reverse the protective effects, confirming Robo1 as the functional receptor. Recombinant protein administration, decoy receptor approach, siRNA knockdown, Cdc42 activity assay, immunohistochemistry, brain edema measurement (rat model) Neurobiology of disease High 26550694
2015 Slit2/Robo1 signaling promotes intestinal tumorigenesis through Src-mediated activation of Wnt/β-catenin signaling by downregulating E-cadherin; this was demonstrated in Slit2 transgenic mice, ApcMin/+ spontaneous adenoma models, and a DMH/DSS colorectal carcinoma model. Slit2 transgenic mice, ApcMin/+ model, DMH/DSS model, Src signaling analysis, E-cadherin/β-catenin Western blot Oncotarget High 25605242
2015 Slit2 promotes angiogenesis via the Robo1-VEGFR2-ERK1/2 pathway; Slit2 overexpression upregulates Robo1 and VEGFR2 and activates phospho-ERK1/2 in both transgenic mice and HUVECs in vitro. Slit2 transgenic mice, plasmid transfection in HUVECs, Western blot (ERK1/2, AKT, p38), cell proliferation/migration/tube formation assays Investigative ophthalmology & visual science Medium 26244297
2016 The integrated heparan sulfate (HS) ligand requirement of Robo1 was determined: Robo1 prefers octasaccharides with 6-O-sulfate esters critical for binding, while C-2 sulfate esters reduce binding; a second low-affinity HS binding site exists at the N-terminus of Robo1, and high-affinity HS ligands can reverse Slit2-Robo1-mediated inhibition of endothelial cell migration. Affinity enrichment of HS oligosaccharides, HILIC-HRMS, permethylation/desulfation MS/MS, chemical synthesis, SPR binding assay, endothelial cell migration assay Journal of the American Chemical Society High 27611601
2016 NMR characterization of glycosylated Robo1-Ig1-2 interaction with a synthetic HS tetramer identified K81 as part of the binding site (Kd ~255 µM); the bound HS conformation, binding epitope, and role of each glycan residue were characterized. Single amino acid type labeling NMR, STD-NMR, trNOE, paramagnetic perturbation, chemical shift perturbation mapping ACS chemical biology High 27653286
2016 Dscam1 forms a complex with Robo1 dependent on the N-terminal fragment of Slit (Slit-N); Dscam1 modifies the output of Robo/Slit complexes so that signaling is no longer repulsive but promotes longitudinal axon growth, as shown in Drosophila. Biochemical co-immunoprecipitation, genetic double mutants (Dscam1/robo1), slit cleavage allele (slit-UC), transgenic rescue experiments (Drosophila) PLoS biology High 27654876
2016 SLIT2/ROBO1 signaling regulates cell shape and matrix adhesion in response to ECM stiffness; Robo1 ablation in the mammary gland compromises actin stress fiber assembly and inhibits cell contractility, while SLIT2 treatment stimulates Rac and increases focal adhesion kinase (FAK) activity to enhance cell tension; stiff ECM increases Robo1 levels by downregulating miR-203. Robo1 ablation in vivo, SLIT2 treatment, Rac activation assay, FAK activity assay, actin cytoskeleton imaging, ECM stiffness manipulation, miR-203 modulation The Journal of cell biology High 26975850
2016 Robo1 promotes cell migration via Cdc42 and Rac1 GTPases; Src activates Abl kinase to stabilize Robo1 protein levels, and inhibition of Abl kinase by siRNA or kinase blockers decreases Robo1 protein and suppresses transformed cell migration. siRNA knockdown of Abl, kinase inhibitors, Western blot for Robo1, GTPase activity assays, cell migration assays Oncotarget Medium 21301049
2016 CdGAP (a Rac1- and Cdc42-specific GTPase-activating protein) is identified as a Robo1-interacting protein in HUVECs; Slit2/Robo1 binding drives endothelial cell migration through Robo1-CdGAP interaction, while Robo4 negatively regulates this signaling intracellularly. Targeted proteomics with anti-Robo1 monoclonal antibody, co-immunoprecipitation, Boyden chamber migration assay, Robo1/Robo4 knockdown Biochemical and biophysical research communications Medium 26713366
2018 Crystal structure of Robo1 Ig1-4 and Ig5 combined with negative stain EM reconstruction shows that the Robo1 ectodomain forms compact dimers mediated by central Ig domains, which further interact 'back-to-back' to generate tetramers; Slit2-N binding does not change Robo1 oligomerization state, suggesting Slit2-N induces a conformational change rather than oligomerization to trigger signaling. X-ray crystallography, negative stain electron microscopy reconstruction, fluorescent imaging of Robo1 oligomerization upon Slit2-N interaction, SAXS Structure (London, England : 1993) High 29307485
2018 The SLIT2/ROBO1 axis contributes to the Warburg effect in osteosarcoma via activation of the SRC/ERK/c-MYC/PFKFB2 pathway; in vitro and in vivo experiments show SLIT2/ROBO1 promotes proliferation, inhibits apoptosis, and alters metabolic reprogramming. In vitro cell assays, in vivo xenograft, Western blot for SRC/ERK/c-MYC/PFKFB2 pathway components, ROBO1 knockdown/overexpression Cell death & disease Medium 29523788
2018 miR-92 binds to the 3' UTR of Robo1 mRNA to suppress its translation (not mRNA degradation) in commissural neurons; disruption of miR-92/Robo1 3'UTR interaction induces premature Slit2 repulsion responsiveness of precrossing commissural axons in vitro and causes axon projection defects in vivo. 3'UTR reporter assay, miR-92 overexpression/inhibition, in vitro Slit2 repulsion assay, in vivo commissural axon guidance (chick) Cell reports High 30184503
2019 NOVA splicing factors regulate temporal expression of mammalian ROBO1 and ROBO2 variants via alternative splicing at a conserved microexon, producing isoforms with distinct guidance activities; ROBO-mediated repulsion is activated early via one isoform to prevent premature crossing and inhibited later to allow crossing, then disinhibited postcrossing. Alternative splicing analysis, NOVA splicing factor genetics, commissural axon guidance assays, isoform-specific rescue experiments (mouse) eLife High 31392959
2019 Recombinant Slit2 reduces neuronal apoptosis after neonatal hypoxic-ischemic encephalopathy via the Robo1-srGAP1 pathway, mediating inhibition of RhoA; decoy Robo1 and srGAP1 siRNA reverse the neuroprotective effects. Recombinant protein administration, decoy receptor, srGAP1 siRNA, RhoA activity assay, TUNEL staining, Western blot (rat neonatal HIE model) Neuropharmacology Medium 31356825
2020 SLIT2 inhibits macropinocytosis in macrophages and RAS-transformed cancer cells via ROBO1-mediated cytoskeletal changes; in vivo, SLIT2 attenuates muramyl dipeptide uptake to prevent NOD2-dependent NF-κB activation and CXCL1 secretion, and blocking endogenous SLIT2 enhances CXCL1 secretion. In vitro macropinocytosis assay, in vivo muramyl dipeptide uptake, NF-κB reporter assay, ELISA, ROBO1 blocking experiments, cytoskeletal imaging Nature communications High 32807784
2020 PRRG4 promotes breast cancer metastasis by recruiting the E3 ubiquitin ligase NEDD4 via its LPSY and PPPY motifs, leading to ubiquitination and degradation of Robo1, thereby activating Src and FAK signaling. Co-immunoprecipitation, domain-mutant constructs (LPSY/PPPY motif mutations), ubiquitination assay, Western blot, migration/invasion assays, in vivo metastasis model Oncogene High 33037408
2021 YY1 directly binds the promoter region of ROBO1 to promote its transcription; ROBO1 inhibits pancreatic cancer proliferation via the CCNA2/CDK2 axis, causing S-phase arrest. Luciferase reporter gene assay, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), ROBO1 overexpression, flow cytometry (cell cycle), subcutaneous xenograft in nude mice Oncogene High 33714986
2024 PTP4A2 (protein tyrosine phosphatase 4A2) modulates self-renewal, proliferation and tumorigenicity in recurrent glioblastoma through a dephosphorylation axis with ROBO1; genetic perturbation or small-molecule inhibition of PTP4A2 exploits functional dependency on ROBO1 signaling, and ROBO1 CAR T cells targeting this receptor doubled median survival in CDX models of recurrent GBM. Genome-wide CRISPR screens, integrative genomic analyses, small-molecule PTP4A2 inhibition, ROBO1-targeted CAR T cell engineering, CDX xenograft models Nature medicine High 39095594
2012 Slit2N (active N-terminal Slit2 fragment) acting through Robo1 inhibits HIV-gp120-induced migration and podosome formation in immature dendritic cells by inducing Robo1 to bind and sequester WASp and LSP1 from β-actin, and by inhibiting Src signaling and downstream Rac1, Pyk2, paxillin, and CDC42 activation. Co-immunoprecipitation, podosome formation assay, transendothelial migration assay, Western blot for Src/Rac1/Pyk2/paxillin/CDC42, siRNA knockdown PloS one Medium 23119100
2020 Slit2/Robo1 signaling promotes the survival of intestinal Lgr5+ stem cells under colitis conditions by activating autophagy; Slit2 transgenic mice show increased LC3II/I ratio and maintained Lgr5+ stem cell proliferation, while Robo1/2 partial knockout reduces Lgr5+ stem cells and decreases autophagy markers. DSS-induced colitis model, Slit2 transgenic and Robo1/2 heterozygous knockout mice, LC3II/I ratio Western blot, p62 Western blot, Lgr5+ immunofluorescence, qPCR International journal of biological sciences Medium 32398956

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS genetics 379 20300657
2011 MiR-218 suppresses nasopharyngeal cancer progression through downregulation of survivin and the SLIT2-ROBO1 pathway. Cancer research 243 21385904
2006 Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain. Development (Cambridge, England) 210 16690755
2015 Slit2 signaling through Robo1 and Robo2 is required for retinal neovascularization. Nature medicine 156 25894826
2001 Inadequate lung development and bronchial hyperplasia in mice with a targeted deletion in the Dutt1/Robo1 gene. Proceedings of the National Academy of Sciences of the United States of America 130 11734623
2012 Activation of Robo1 signaling of breast cancer cells by Slit2 from stromal fibroblast restrains tumorigenesis via blocking PI3K/Akt/β-catenin pathway. Cancer research 128 22826604
2007 Slit2 involvement in glioma cell migration is mediated by Robo1 receptor. Journal of neuro-oncology 104 17968499
2010 Collaborative and specialized functions of Robo1 and Robo2 in spinal commissural axon guidance. The Journal of neuroscience : the official journal of the Society for Neuroscience 98 20631173
2002 Tumour specific promoter region methylation of the human homologue of the Drosophila Roundabout gene DUTT1 (ROBO1) in human cancers. Oncogene 98 12082532
2011 SLIT/ROBO1 signaling suppresses mammary branching morphogenesis by limiting basal cell number. Developmental cell 87 21664580
2006 Identification of ROBO1 as a novel hepatocellular carcinoma antigen and a potential therapeutic and diagnostic target. Clinical cancer research : an official journal of the American Association for Cancer Research 86 16740745
2018 SLIT2/ROBO1 axis contributes to the Warburg effect in osteosarcoma through activation of SRC/ERK/c-MYC/PFKFB2 pathway. Cell death & disease 82 29523788
2015 Activation of Slit2-Robo1 signaling promotes liver fibrosis. Journal of hepatology 81 26264936
2007 Frequent inactivation of RAMP2, EFEMP1 and Dutt1 in lung cancer by promoter hypermethylation. Clinical cancer research : an official journal of the American Association for Cancer Research 74 17671114
2014 FLRT3 is a Robo1-interacting protein that determines Netrin-1 attraction in developing axons. Current biology : CB 70 24560577
2015 Robo2 acts in trans to inhibit Slit-Robo1 repulsion in pre-crossing commissural axons. eLife 69 26186094
2006 Robo1/Robo4: differential expression of angiogenic markers in colorectal cancer. Oncology reports 66 16685377
2014 Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling. Nature communications 62 25030704
2012 The lhx2 transcription factor controls thalamocortical axonal guidance by specific regulation of robo1 and robo2 receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 57 22457488
2012 RabGDI controls axonal midline crossing by regulating Robo1 surface expression. Neural development 57 23140504
1998 The DUTT1 gene, a novel NCAM family member is expressed in developing murine neural tissues and has an unusually broad pattern of expression. Molecular and cellular neurosciences 57 9608531
2013 MicroRNA 203 Modulates Glioma Cell Migration via Robo1/ERK/MMP-9 Signaling. Genes & cancer 51 24167656
2015 High structural resolution hydroxyl radical protein footprinting reveals an extended Robo1-heparin binding interface. The Journal of biological chemistry 50 25752613
2010 Human ROBO1 is cleaved by metalloproteinases and gamma-secretase and migrates to the nucleus in cancer cells. FEBS letters 50 20471383
2017 miR-218 inhibited tumor angiogenesis by targeting ROBO1 in gastric cancer. Gene 48 28323002
2016 Fruitless Represses robo1 Transcription to Shape Male-Specific Neural Morphology and Behavior in Drosophila. Current biology : CB 48 27265393
2010 Slit2/Robo1 signaling in glioma migration and invasion. Neuroscience bulletin 48 21113198
2004 Targeted disruption of the 3p12 gene, Dutt1/Robo1, predisposes mice to lung adenocarcinomas and lymphomas with methylation of the gene promoter. Cancer research 48 15374951
2014 Robo1 modulates proliferation and neurogenesis in the developing neocortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 46 24741061
2009 Increased immunoreactivity to SLIT/ROBO1 in ovarian endometriomas: a likely constituent biomarker for recurrence. The American journal of pathology 45 19608877
2015 Mammary Stem Cell Self-Renewal Is Regulated by Slit2/Robo1 Signaling through SNAI1 and mINSC. Cell reports 44 26440891
2010 The corticofugal neuron-associated genes ROBO1, SRGAP1, and CTIP2 exhibit an anterior to posterior gradient of expression in early fetal human neocortex development. Cerebral cortex (New York, N.Y. : 1991) 44 21060114
2020 SLIT2/ROBO1-signaling inhibits macropinocytosis by opposing cortical cytoskeletal remodeling. Nature communications 43 32807784
2018 MicroRNA-365 promotes lung carcinogenesis by downregulating the USP33/SLIT2/ROBO1 signalling pathway. Cancer cell international 41 29743814
2016 Integrated Approach to Identify Heparan Sulfate Ligand Requirements of Robo1. Journal of the American Chemical Society 40 27611601
2015 SLIT2/ROBO1-miR-218-1-RET/PLAG1: a new disease pathway involved in Hirschsprung's disease. Journal of cellular and molecular medicine 40 25786906
2004 Dynamic expression patterns of Robo (Robo1 and Robo2) in the developing murine central nervous system. The Journal of comparative neurology 40 14689480
2016 Dscam1 Forms a Complex with Robo1 and the N-Terminal Fragment of Slit to Promote the Growth of Longitudinal Axons. PLoS biology 38 27654876
2015 Slit2/Robo1 signaling promotes intestinal tumorigenesis through Src-mediated activation of the Wnt/β-catenin pathway. Oncotarget 38 25605242
2012 Robo1 regulates the migration and laminar distribution of upper-layer pyramidal neurons of the cerebral cortex. Cerebral cortex (New York, N.Y. : 1991) 38 22661412
2015 Recombinant Slit2 attenuates neuroinflammation after surgical brain injury by inhibiting peripheral immune cell infiltration via Robo1-srGAP1 pathway in a rat model. Neurobiology of disease 37 26550694
2015 Slit2 Promotes Angiogenic Activity Via the Robo1-VEGFR2-ERK1/2 Pathway in Both In Vivo and In Vitro Studies. Investigative ophthalmology & visual science 36 26244297
2013 The microRNA-218 and ROBO-1 signaling axis correlates with the lymphatic metastasis of pancreatic cancer. Oncology reports 36 23733161
2014 ROBO1, a tumor suppressor and critical molecular barrier for localized tumor cells to acquire invasive phenotype: study in African-American and Caucasian prostate cancer models. International journal of cancer 35 24752651
2014 MicroRNA-218 inhibits cell invasion and migration of pancreatic cancer via regulating ROBO1. Cancer biology & therapy 35 25010661
2017 Mutations in the Human ROBO1 Gene in Pituitary Stalk Interruption Syndrome. The Journal of clinical endocrinology and metabolism 34 28402530
2016 Loss of miR-203 regulates cell shape and matrix adhesion through ROBO1/Rac/FAK in response to stiffness. The Journal of cell biology 34 26975850
2012 Silencing of miRNA-218 promotes migration and invasion of breast cancer via Slit2-Robo1 pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 34 22898079
2020 Slit2/Robo1 Mitigates DSS-induced Ulcerative Colitis by Activating Autophagy in Intestinal Stem Cell. International journal of biological sciences 32 32398956
2002 Temporal and spatial expression of two isoforms of the Dutt1/Robo1 gene in mouse development. FEBS letters 31 12123796
2017 Loss of function in ROBO1 is associated with tetralogy of Fallot and septal defects. Journal of medical genetics 30 28592524
2017 MiR-490-5p Inhibits Hepatocellular Carcinoma Cell Proliferation, Migration and Invasion by Directly Regulating ROBO1. Pathology oncology research : POR 30 28924964
2016 srGAP1 mediates the migration inhibition effect of Slit2-Robo1 in colorectal cancer. Journal of experimental & clinical cancer research : CR 30 27923383
2019 Temporal regulation of axonal repulsion by alternative splicing of a conserved microexon in mammalian Robo1 and Robo2. eLife 29 31392959
2018 Robo1 Forms a Compact Dimer-of-Dimers Assembly. Structure (London, England : 1993) 29 29307485
2018 miR-92 Suppresses Robo1 Translation to Modulate Slit Sensitivity in Commissural Axon Guidance. Cell reports 29 30184503
2015 miR-1179 promotes cell invasion through SLIT2/ROBO1 axis in esophageal squamous cell carcinoma. International journal of clinical and experimental pathology 29 25755718
2011 Influence of ROBO1 and RORA on risk of age-related macular degeneration reveals genetically distinct phenotypes in disease pathophysiology. PloS one 29 21998696
2015 miR-218 inhibits the migration and invasion of glioma U87 cells through the Slit2-Robo1 pathway. Oncology letters 28 25789001
2015 MicroRNA-219-5p exerts tumor suppressor function by targeting ROBO1 in glioblastoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 28 26081620
2014 Association of the ROBO1 gene with reading disabilities in a family-based analysis. Genes, brain, and behavior 28 24612512
2024 Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells. Nature medicine 27 39095594
2020 Dynamic expression of Slit1-3 and Robo1-2 in the mouse peripheral nervous system after injury. Neural regeneration research 27 31719262
2020 PRRG4 promotes breast cancer metastasis through the recruitment of NEDD4 and downregulation of Robo1. Oncogene 27 33037408
2013 Characterization of the interaction between Robo1 and heparin and other glycosaminoglycans. Biochimie 27 23994753
2023 Coadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma. Nature communications 26 36792623
2020 Long non-coding RNA LINC00473 acts as a microRNA-29a-3p sponge to promote hepatocellular carcinoma development by activating Robo1-dependent PI3K/AKT/mTOR signaling pathway. Therapeutic advances in medical oncology 26 32922520
2020 Crosstalk between the activated Slit2-Robo1 pathway and TGF-β1 signalling promotes cardiac fibrosis. ESC heart failure 26 33236535
2015 Robo1 promotes angiogenesis in hepatocellular carcinoma through the Rho family of guanosine triphosphatases' signaling pathway. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 26 26022159
2023 Slit2/Robo1 signaling inhibits small-cell lung cancer by targeting β-catenin signaling in tumor cells and macrophages. Molecular oncology 24 35838343
2012 Slit2N/Robo1 inhibit HIV-gp120-induced migration and podosome formation in immature dendritic cells by sequestering LSP1 and WASp. PloS one 24 23119100
2022 Tumor-Derived Exosomal miR-29b Reduces Angiogenesis in Pancreatic Cancer by Silencing ROBO1 and SRGAP2. Journal of immunology research 23 36277474
2021 Roundabout homolog 1 inhibits proliferation via the YY1-ROBO1-CCNA2-CDK2 axis in human pancreatic cancer. Oncogene 22 33714986
2020 Id Proteins Promote a Cancer Stem Cell Phenotype in Mouse Models of Triple Negative Breast Cancer via Negative Regulation of Robo1. Frontiers in cell and developmental biology 22 32766238
2016 Structural Aspects of Heparan Sulfate Binding to Robo1-Ig1-2. ACS chemical biology 22 27653286
2014 Inhibition of endothelial Slit2/Robo1 signaling by thalidomide restrains angiogenesis by blocking the PI3K/Akt pathway. Digestive diseases and sciences 22 25326112
2013 Frameshift mutations of axon guidance genes ROBO1 and ROBO2 in gastric and colorectal cancers with microsatellite instability. Pathology 22 24247621
2010 Effect of Robo1 on retinal pigment epithelial cells and experimental proliferative vitreoretinopathy. Investigative ophthalmology & visual science 22 20071679
2015 Suppression of Slit2/Robo1 mediated HUVEC migration by Robo4. Biochemical and biophysical research communications 21 26713366
2014 A (90)Y-labelled anti-ROBO1 monoclonal antibody exhibits antitumour activity against hepatocellular carcinoma xenografts during ROBO1-targeted radioimmunotherapy. EJNMMI research 21 25006547
2010 Src activates Abl to augment Robo1 expression in order to promote tumor cell migration. Oncotarget 21 21301049
2018 Robo1 and vimentin regulate radiation-induced motility of human glioblastoma cells. PloS one 20 29864155
2017 Slit2/Robo1 promotes synaptogenesis and functional recovery of spinal cord injury. Neuroreport 20 27893610
2011 Increased immunoreactivity to SLIT/ROBO1 and its correlation with severity of dysmenorrhea in adenomyosis. Fertility and sterility 20 20970134
2016 Slit2 and Robo1 induce opposing effects on metastasis of hepatocellular carcinoma Sk-hep-1 cells. International journal of oncology 19 27176045
2015 SYD-1C, UNC-40 (DCC) and SAX-3 (Robo) function interdependently to promote axon guidance by regulating the MIG-2 GTPase. PLoS genetics 19 25876065
2019 Activation of Slit2/Robo1 Signaling Promotes Tumor Metastasis in Colorectal Carcinoma through Activation of the TGF-β/Smads Pathway. Cells 18 31242633
2008 Robo1/robo4: different expression patterns in retinal development. Experimental eye research 18 19084519
2021 Raddeanin A inhibits proliferation, invasion, migration and promotes apoptosis of cervical cancer cells via regulating miR-224-3p/Slit2/Robo1 signaling pathway. Aging 17 33621954
2017 Compound Heterozygous Variants in ROBO1 Cause a Neurodevelopmental Disorder With Absence of Transverse Pontine Fibers and Thinning of the Anterior Commissure and Corpus Callosum. Pediatric neurology 17 28286008
2017 Brief Report: Robo1 Regulates the Migration of Human Subventricular Zone Neural Progenitor Cells During Development. Stem cells (Dayton, Ohio) 17 28406573
2016 MiR-218 inhibits the tumorgenesis and proliferation of glioma cells by targeting Robo1. Cancer biomarkers : section A of Disease markers 17 26889813
2018 Implication of SLIT3-ROBO1/ROBO2 in granulosa cell proliferation, differentiation and follicle selection in the prehierarchical follicles of hen ovary. Cell biology international 16 30288875
2015 Role of Slit2/Robo1 in trophoblast invasion and vascular remodeling during ectopic tubal pregnancy. Placenta 16 26282852
2014 Crystal structure of the extracellular juxtamembrane region of Robo1. Journal of structural biology 16 24607414
2022 Glial-secreted Netrins regulate Robo1/Rac1-Cdc42 signaling threshold levels during Drosophila asymmetric neural stem/progenitor cell division. Current biology : CB 15 35472309
2019 Recombinant Slit2 attenuates neuronal apoptosis via the Robo1-srGAP1 pathway in a rat model of neonatal HIE. Neuropharmacology 15 31356825
2017 Alterted SLIT2/ROBO1 signalling is linked to impaired placentation of missed and threatened miscarriage in early pregnancy. Histopathology 15 28485101
2015 Robo1/2 regulate follicle atresia through manipulating granulosa cell apoptosis in mice. Scientific reports 15 25988316
2013 Slit/Robo1 signaling regulates neural tube development by balancing neuroepithelial cell proliferation and differentiation. Experimental cell research 15 23438940