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    ROBO4 roundabout guidance receptor 4 [ Homo sapiens (human) ]

    Gene ID: 54538, updated on 5-Mar-2024

    Summary

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    Official Symbol
    ROBO4provided by HGNC
    Official Full Name
    roundabout guidance receptor 4provided by HGNC
    Primary source
    HGNC:HGNC:17985
    See related
    Ensembl:ENSG00000154133 MIM:607528; AllianceGenome:HGNC:17985
    Gene type
    protein coding
    RefSeq status
    VALIDATED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    MRB; AOVD3; ECSM4
    Summary
    Predicted to enable cell-cell adhesion mediator activity. Involved in angiogenesis and establishment of endothelial barrier. Located in extracellular exosome. Implicated in aortic valve disease 3. [provided by Alliance of Genome Resources, Apr 2022]
    Expression
    Broad expression in fat (RPKM 35.9), spleen (RPKM 32.4) and 17 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    Location:
    11q24.2
    Exon count:
    18
    Annotation release Status Assembly Chr Location
    RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 11 NC_000011.10 (124883691..124897865, complement)
    RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 11 NC_060935.1 (124912311..124926485, complement)
    105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 11 NC_000011.9 (124753587..124767761, complement)

    Chromosome 11 - NC_000011.10Genomic Context describing neighboring genes Neighboring gene MSANTD2 antisense RNA 1 Neighboring gene E3 ubiquitin-protein ligase RNF181-like Neighboring gene H3K4me1 hESC enhancer GRCh37_chr11:124712489-124713052 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr11:124713053-124713614 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr11:124732803-124733304 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr11:124735644-124736320 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr11:124738370-124738900 Neighboring gene Sharpr-MPRA regulatory region 2144 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4035 Neighboring gene roundabout guidance receptor 3 Neighboring gene Sharpr-MPRA regulatory region 10426 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr11:124756054-124756568 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr11:124756569-124757082 Neighboring gene uncharacterized LOC107984406 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr11:124767654-124768276 Neighboring gene hepatic and glial cell adhesion molecule Neighboring gene hepatocellular carcinoma, down-regulated 1 Neighboring gene H3K27ac hESC enhancer GRCh37_chr11:124823758-124824301 Neighboring gene CCDC15 divergent transcript

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. Downregulation of ROBO4 in Pancreatic Cancer Serves as a Biomarker of Poor Prognosis and Indicates Increased Cell Motility and Proliferation Through Activation of MMP-9. Yamanaka M, et al. Ann Surg Oncol, 2022 Oct. PMID 35726111
    2. PRC2 Components Maintain DNA Hypermethylation of the Upstream Promoter and Regulate Robo4 Expression in Endothelial Cells. Izawa K, et al. Biol Pharm Bull, 2020. PMID 32238717
    3. Regulatory mechanisms of Robo4 and their effects on angiogenesis. Dai C, et al. Biosci Rep, 2019 Jul 31. PMID 31160487, Free PMC Article
    4. Robo 4 - the double-edged sword in prostate cancer: impact on cancer cell aggressiveness and tumor vasculature. Pircher A, et al. Int J Med Sci, 2019. PMID 30662335, Free PMC Article
    5. Validation of RT-qPCR reference genes and determination of Robo4 expression levels in human retinal endothelial cells under hypoxia and/or hyperglycemia. Xie J, et al. Gene, 2016 Jul 1. PMID 27041242

    See all (64) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. The role of TET2-mediated ROBO4 hypomethylation in the development of diabetic retinopathy.
      Title: The role of TET2-mediated ROBO4 hypomethylation in the development of diabetic retinopathy.
    2. Downregulation of ROBO4 in Pancreatic Cancer Serves as a Biomarker of Poor Prognosis and Indicates Increased Cell Motility and Proliferation Through Activation of MMP-9.
      Title: Downregulation of ROBO4 in Pancreatic Cancer Serves as a Biomarker of Poor Prognosis and Indicates Increased Cell Motility and Proliferation Through Activation of MMP-9.
    3. Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease.
      Title: Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease.
    4. miR-140-5p regulates vascular smooth muscle cell viability, migration and apoptosis by targeting ROBO4 gene expression in atherosclerosis.
      Title: miR-140-5p regulates vascular smooth muscle cell viability, migration and apoptosis by targeting ROBO4 gene expression in atherosclerosis.
    5. Structural insights and evaluation of the potential impact of missense variants on the interactions of SLIT2 with ROBO1/4 in cancer progression.
      Title: Structural insights and evaluation of the potential impact of missense variants on the interactions of SLIT2 with ROBO1/4 in cancer progression.
    6. Nuclear Localization of Robo is Associated with Better Survival in Bladder Cancer.
      Title: Nuclear Localization of Robo is Associated with Better Survival in Bladder Cancer.
    7. PRC2 Components Maintain DNA Hypermethylation of the Upstream Promoter and Regulate Robo4 Expression in Endothelial Cells.
      Title: PRC2 Components Maintain DNA Hypermethylation of the Upstream Promoter and Regulate Robo4 Expression in Endothelial Cells.
    8. Regulatory mechanisms of Robo4 and their effects on angiogenesis.
      Title: Regulatory mechanisms of Robo4 and their effects on angiogenesis.
    9. VEGF and Robo4 were co-expressed in FVMs from proliferative diabetic retinopathy (PDR) patients. In the early stages, VEGF was upregulated and contributed to retinopahy development, whereas, in the late stage, VEGF and Robo4 worked together to aggravate disease progression. However, miR-15a could downregulate VEGF and Robo4 to ameliorate Diabetic retinopathy development.
      Title: Upregulated VEGF and Robo4 correlate with the reduction of miR-15a in the development of diabetic retinopathy.
    10. In human brain endothelial cells that were damaged by hypoxia plus IL-1beta, treatment with recombinant ANXA2 (rA2) rescued the expression of junctional proteins and decreased trans-endothelial permeability. The protective effects were mediated in part by interactions with F-actin and VE-cadherin, and the ability of rA2 to modulate signaling via Robo4 -paxillin- ARF6.
      Title: Annexin A2 is a Robo4 ligand that modulates ARF6 activation-associated cerebral trans-endothelial permeability.
    Submit: New GeneRIF Correction See all GeneRIFs (46)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Associated conditions

    Description Tests
    Aortic valve disease 3
    MedGen: C5193127 OMIM: 618496 GeneReviews: Not available
    		Compare labs

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Genotypes

    HIV-1 interactions

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    Protein interactions

    Protein Gene Interaction Pubs
    Envelope surface glycoprotein gp120 env Interaction of SLIT2 with Robo4 significantly inhibits HIV-1 gp120-induced phosphorylation of c-Src in human lymphatic endothelial cells PubMed
    env HIV-1 gp120 induces phosphorylation of fibronectin and enhances a physical association between fibronectin and Robo4 in human lymphatic endothelial cells PubMed
    env The fibronectin domains of Robo4 are critical for HIV-1 gp120-induced hyperpermeability of human lymphatic endothelial cell monolayers PubMed

    Go to the HIV-1, Human Interaction Database

    Pathways from PubChem

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    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ20798, MGC133352, MGC133353

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables cell-cell adhesion mediator activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables signaling receptor activity TAS
    Traceable Author Statement
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in angiogenesis IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in axon guidance IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in dendrite self-avoidance IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in establishment of endothelial barrier IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in homophilic cell adhesion via plasma membrane adhesion molecules IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in regulation of cell migration NAS
    Non-traceable Author Statement
    more info
    		 PubMed 
    Component Evidence Code Pubs
    is_active_in axon IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in extracellular exosome HDA PubMed 
    located_in membrane TAS
    Traceable Author Statement
    more info
    		 PubMed 
    is_active_in plasma membrane IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  

    General protein information

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    Preferred Names
    roundabout homolog 4
    Names
    roundabout homolog 4, magic roundabout
    roundabout, axon guidance receptor, homolog 4

    NCBI Reference Sequences (RefSeq)

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    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    mRNA and Protein(s)

    1. NM_001301088.2 → NP_001288017.1  roundabout homolog 4 isoform 2

      See identical proteins and their annotated locations for NP_001288017.1

      Status: VALIDATED

      Description
      Transcript Variant: This variant (2) uses an alternate splice junction at the 5' end of the second exon and starts translation at a downstream AUG compared to variant 1. The resulting isoform (2) is shorter at the N-terminus compared to isoform 1.
      Source sequence(s)
      AF361473, AK302628, AP003501, DC424813
      Consensus CDS
      CCDS73409.1
      UniProtKB/TrEMBL
      B4DYV8
      Related
      ENSP00000437129.1, ENST00000533054.5
      Conserved Domains (3) summary
      smart00410
      Location:1 → 75
      IG_like; Immunoglobulin like
      pfam00041
      Location:205 → 287
      fn3; Fibronectin type III domain
      cl11960
      Location:1 → 80
      Ig; Immunoglobulin domain

    2. NM_019055.6 → NP_061928.4  roundabout homolog 4 isoform 1 precursor

      See identical proteins and their annotated locations for NP_061928.4

      Status: VALIDATED

      Description
      Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).
      Source sequence(s)
      AF361473, AP003501, DC424813
      Consensus CDS
      CCDS8455.1
      UniProtKB/Swiss-Prot
      A8K154, Q14DU7, Q8TEG1, Q8WZ75, Q96JV6, Q9H718, Q9NWJ8
      Related
      ENSP00000304945.3, ENST00000306534.8
      Conserved Domains (4) summary
      cd05724
      Location:141 → 225
      Ig2_Robo; Second immunoglobulin (Ig)-like domain in Robo (roundabout) receptors
      pfam07679
      Location:139 → 220
      I-set; Immunoglobulin I-set domain
      pfam00041
      Location:350 → 432
      fn3; Fibronectin type III domain
      cl11960
      Location:31 → 133
      Ig; Immunoglobulin domain

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000011.10 Reference GRCh38.p14 Primary Assembly

      Range
      124883691..124897865 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_006718861.3 → XP_006718924.1  roundabout homolog 4 isoform X1

      Conserved Domains (4) summary
      cd05724
      Location:141 → 225
      Ig2_Robo; Second immunoglobulin (Ig)-like domain in Robo (roundabout) receptors
      pfam07679
      Location:139 → 220
      I-set; Immunoglobulin I-set domain
      pfam00041
      Location:350 → 432
      fn3; Fibronectin type III domain
      cl11960
      Location:31 → 133
      Ig; Immunoglobulin domain

    2. XM_011542875.2 → XP_011541177.1  roundabout homolog 4 isoform X2

      Conserved Domains (1) summary
      PHA03247
      Location:125 → 434
      PHA03247; large tegument protein UL36; Provisional

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060935.1 Alternate T2T-CHM13v2.0

      Range
      124912311..124926485 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054369168.1 → XP_054225143.1  roundabout homolog 4 isoform X1

    2. XM_054369169.1 → XP_054225144.1  roundabout homolog 4 isoform X2

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q8WZ75.1 GenPept UniProtKB/Swiss-Prot:Q8WZ75

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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