ROBO1 (roundabout, axon guidance receptor, homolog 1 (Drosophila))

2008-12-01   Joern Groene , Oliver Doebler 

Identity

HGNC
LOCATION
3p12.3
LOCUSID
ALIAS
DUTT1,SAX3
FUSION GENES

DNA/RNA

Atlas Image

Description

30 Exons, 30 coding exons, 992672bp of genomic DNA.

Transcription

Two mRNA transcript variants. Transcript variant 1 contains of 6629b coded by 30 exons. Transcript variant 2 utilizes an alternate exon that contains a different 5UTR and translation start site than that of variant 1. The N-terminus differs from isoform a encoded by variant 1. Transcript variant 2 contains of 6456b coded by 28 exons.

Pseudogene

None known.

Proteins

Description

ROBO1 is a single-pass type 1 membrane protein and interacts with SLIT1 and SLIT2. ROBO1 belongs to the immunglobulin super family of ROBO proteins. It contains of 3 fibronectin type-III domains and 5 immunoglobuline-like C2-type domains. There are 3 protein isoforms existing of ROBO1 produced by alternative splicing.

Expression

ROBO1 expression is seen in a number different tissues and organs.

Localisation

ROBO1 proteins are located in the cellular membrane as a transmembrane protein.

Function

Receptor for SLIT1 and SLIT2 which are thought to act as molecular guidance cue in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuronal development. In axon growth cones, the silencing of the attractive effect of NTN1 by SLIT2 may require the formation of a ROBO1-DCC complex. Robo1 plays also a role in cell-adhesion. ROBO1 may be required for lung development. It is indicated that ROBO/SLIT is involved in angiogenic mechanisms whereas endothelial cells expressing ROBO1 receptors are attracted by SLIT2 which is secreted by human tumor cells.

Homology

There are 3 paralogs of human ROBO1 : ROBO2, ROBO3 and ROBO4. Orthologs have been identified in mouse, rat, cow, dog, chimpanzee.

Implicated in

Entity name
Lung cancer
Oncogenesis
A deletion of chromosome 3 allele and dysfunction or lack of ROBO1 receptors might be an early somatic genetic change in lung tumor development (Xian et al., 2001; Dallol et al., 2002b; Tsujiuchi et al., 2004; Xian et al., 2004).
Entity name
Breast cancer
Oncogenesis
Breast cancer tumors and tumor cell lines show a suppressed expression of ROBO1 gene (Dallol et al., 2002a; Dallol et al., 2002b).
Entity name
Prostate cancer
Oncogenesis
Human prostate tumors and tumor cell lines show an overexpression of ROBO1 gene (Bonner et al., 2003).
Entity name
Angiogenesis of malignant tumors
Oncogenesis
ROBO1 gene is highly expressed in tumor vessel endothelium. Blocking of ROBO1 receptors causes loss of microvessel density in tumors e.g. malignant melanoma, colorectal cancer (Wang et al., 2003; Suchting et al., 2005; Groene et al., 2006; Legg et al., 2008).
Entity name
Colorectal cancer
Oncogenesis
ROBO1 gene is overexpressed in human colorectal cancer tumor probes and colorectal cancer cell lines (Groene et al., 2006).
Entity name
Cervical cancer
Oncogenesis
Cervical Cancer exhibits highly complex genomic alterations. These include hemizygous deletions at 4p15.3, 10q24, 5q35, 3p12.3, and 11q24, the chromosomal sites of SLIT-ROBO pathway genes (Narayan et al., 2006).
Entity name
Hepatocellular carcinoma
Oncogenesis
ROBO1, a member of the immunoglobulin superfamily, is highly expressed in hepatocellular carcinoma, whereas it showes only a limited distribution in normal liver tissue. Strikingly, the ectodomain of ROBO1 was detected not only in the culture medium of liver cancer cell lines (PLC/PRF/5, HepG2, etc.) but also in sera from hepatocellular carcinoma patients (Ito et al., 2006).
Oncogenesis
ROBO1 gene alterations were detected in subpopulations with childhood T-acute lymphoblastic leukaemia (Haltrich et al., 2007).
Entity name
Nasopharyngeal carcinoma
Oncogenesis
In an inducible Epstein-Barr virus (EBV) nasopharyngeal cell line was a increased expression of ROBO1 detected that may be cause a role in this tumor carcinogenesis (Lee et al., 2008).
Entity name
Dyslexia
Disease
Dyslexia may be caused by partial haplo-insufficiency for ROBO1 in rare families. A slight disturbance in neuronal axon crossing across the midline between brain hemispheres, dendrite guidance, or another function of ROBO1 may manifest as a specific reading disability in humans (Hannula-Jouppi et al., 2005; Fisher and Francks, 2006; McGrath et al., 2006; Shastry, 2007; Paracchini et al., 2007).
Entity name
Autism
Disease
Gene expression analysis show a reduced expression for ROBO1 in the autistic patient group and may play a role in pathogenesis of autism (Anitha et al., 2008).

Bibliography

Pubmed IDLast YearTitleAuthors
182709762008Genetic analyses of roundabout (ROBO) axon guidance receptors in autism.Anitha A et al
128079612003Gene expression signatures identify novel regulatory pathways during murine lung development: implications for lung tumorigenesis.Bonner AE et al
123845512002SLIT2, a human homologue of the Drosophila Slit2 gene, has tumor suppressor activity and is frequently inactivated in lung and breast cancers.Dallol A et al
120825322002Tumour specific promoter region methylation of the human homologue of the Drosophila Roundabout gene DUTT1 (ROBO1) in human cancers.Dallol A et al
166752852006Genes, cognition and dyslexia: learning to read the genome.Fisher SE et al
166853772006Robo1/Robo4: differential expression of angiogenic markers in colorectal cancer.Gröne J et al
171753802007Multipoint interphase FISH in childhood T-acute lymphoblastic leukemia detects subpopulations that carry different chromosome 3 aberrations.Haltrich I et al
162546012005The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia.Hannula-Jouppi K et al
167407452006Identification of ROBO1 as a novel hepatocellular carcinoma antigen and a potential therapeutic and diagnostic target.Ito H et al
124716132003Quantification of expression of netrins, slits and their receptors in human prostate tumors.Latil A et al
186566872008Amplicons on chromosome 3 contain oncogenes induced by recurrent exposure to 12-O-tetradecanoylphorbol-13-acetate and sodium n-butyrate and Epstein-Barr virus reactivation in a nasopharyngeal carcinoma cell line.Lee CH et al
182647862008Slits and Roundabouts in cancer, tumour angiogenesis and endothelial cell migration.Legg JA et al
167818912006Breakthroughs in the search for dyslexia candidate genes.McGrath LM et al
177045642007Production of Slit2 LRR domains in mammalian cells for structural studies and the structure of human Slit2 domain 3.Morlot C et al
167009092006Promoter hypermethylation-mediated inactivation of multiple Slit-Robo pathway genes in cervical cancer progression.Narayan G et al
174448112007The genetic lexicon of dyslexia.Paracchini S et al
170940622006[Genetics of dyslexia].Schulte-Körne G et al
171112662007Developmental dyslexia: an update.Shastry BS et al
154860582005Soluble Robo4 receptor inhibits in vivo angiogenesis and endothelial cell migration.Suchting S et al
152642152004Alterations of the Dutt1/Robo1 gene in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine in rats.Tsujiuchi T et al
128927102003Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity.Wang B et al
182012752008Targeting Slit-Roundabout signaling inhibits tumor angiogenesis in chemical-induced squamous cell carcinogenesis.Wang LJ et al
153749512004Targeted disruption of the 3p12 gene, Dutt1/Robo1, predisposes mice to lung adenocarcinomas and lymphomas with methylation of the gene promoter.Xian J et al
117346232001Inadequate lung development and bronchial hyperplasia in mice with a targeted deletion in the Dutt1/Robo1 gene.Xian J et al

Other Information

Locus ID:

NCBI: 6091
MIM: 602430
HGNC: 10249
Ensembl: ENSG00000169855

Variants:

dbSNP: 6091
ClinVar: 6091
TCGA: ENSG00000169855
COSMIC: ROBO1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000169855ENST00000436010A0A0A0MSX4
ENSG00000169855ENST00000464233Q9Y6N7
ENSG00000169855ENST00000467549Q9Y6N7
ENSG00000169855ENST00000472273H7C545
ENSG00000169855ENST00000492990F8WEV8
ENSG00000169855ENST00000495273Q9Y6N7
ENSG00000169855ENST00000495961H7C4Y7
ENSG00000169855ENST00000618833A0A087WTM1
ENSG00000169855ENST00000618846A0A087WZ85

Expression (GTEx)

0
5
10
15
20
25
30

Pathways

PathwaySourceExternal ID
Axon guidanceKEGGko04360
Axon guidanceKEGGhsa04360
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Netrin-1 signalingREACTOMER-HSA-373752
Signaling by Robo receptorREACTOMER-HSA-376176
Regulation of Commissural axon pathfinding by Slit and RoboREACTOMER-HSA-428542
Inactivation of Cdc42 and RacREACTOMER-HSA-428543
Activation of RacREACTOMER-HSA-428540
Role of Abl in Robo-Slit signalingREACTOMER-HSA-428890

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
203006572010MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor.173
213859042011MiR-218 suppresses nasopharyngeal cancer progression through downregulation of survivin and the SLIT2-ROBO1 pathway.116
162546012005The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia.106
190231252009A genome-wide association study of schizophrenia using brain activation as a quantitative phenotype.104
183875952008On the replication of genetic associations: timing can be everything!72
178485142007Structural insights into the Slit-Robo complex.62
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
170625602006A molecular mechanism for the heparan sulfate dependence of slit-robo signaling.52
179684992008Slit2 involvement in glioma cell migration is mediated by Robo1 receptor.50
210416082011Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up.48

Citation

Joern Groene ; Oliver Doebler

ROBO1 (roundabout, axon guidance receptor, homolog 1 (Drosophila))

Atlas Genet Cytogenet Oncol Haematol. 2008-12-01

Online version: http://atlasgeneticsoncology.org/gene/42140/robo1