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RTN4 (reticulon 4)

Identity

Other namesASY
NI220/250
NOGO
NOGO-A
NSP
NSP-CL
Nbla00271
Nbla10545
RTN-X
RTN4-A
RTN4-B1
RTN4-B2
RTN4-C
HGNC (Hugo) RTN4
LocusID (NCBI) 57142
Location 2p16.1
Location_base_pair Starts at 55199327 and ends at 55237470 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Between FLJ42562 and FLJ31438.
 
  Local order.

DNA/RNA

 
  Genomic structure and transcriptional isoforms.
Description The RTN4 gene spans about 75kb, and contains 9 major exons and several different cap sites (Fig. 2a).
Transcription Three major, RTN4-A, B1 and C, (Fig. 2b) and several minor transcriptional isoforms result from alternative splicing and/or differential promoter usage. Although RTN4 mRNA is ubiquitously expressed, the expression of isoforms is tissue-specific, for example, RTN4-A and C in brain, RTN4-C in muscle, and RTN4-B1 in many other tissues.

Protein

Description Proteins with different sizes are synthesized from different mRNA isoforms: RTN4-A, 129.9 kDa (1192 amino acids); RTN4-B1, 40.3 kDa (373 amino acids); RTN4-B2, 42.3 kDa (392 amino acids); RTN4-C, 22.4 kDa (199 amino acids). All RTN4 protein isoforms retain a common C-terminal domain containing two trans-membrane domains and an endoplasmic reticulum (ER)-retrieval motif.
Expression Ubiquitously expressed (see Transcription).
Localisation RTN4 protein localizes predominantly in the ER and, to a lesser extent, in cytoplasmic membrane.
Function Although definitive functional mechanisms of RTN4 have not yet been clarified, RTN4 protein interacts with several other proteins, including RTN1, RTN3, DP1/Yop1p, BACE1, and Nogo receptor (NogoR). Interaction with DP1/Yop1p, an ER membrane protein, may be necessary for maintenance or stabilization of tubular ER. Binding with BACE1 (beta-amyloid converting enzyme 1) results in reduction in BACE1 activity and production of amyloid-beta. RTN4 also interacts with NogoR, and may lead to activation of RhoA and inhibition of neuronal regeneration in central nervous system. Further, overexpression of RTN4 may cause ER stress and apoptosis in certain cells.
Homology Four reticulon family members (RTN1, RTN2, RTN3 and RTN4) have been identified. They possess a highly conserved C-terminal domain named reticulon homology domain.

Implicated in

Entity Various cancers.
Note Down-regulation of RTN4 expression was observed in small cell lung carcinomas and adult T-cell leukemia/lymphomas, and RTN3, one of RTN4 interacting proteins, was over-expressed in astrocytomas, suggesting involvement of RTN4 (and RTN3) in certain types of tumorigenesis. However, increased incidence of tumor formation has not been observed in RTN4 knock out mice.
RTN4 is also suspected to involve in schizophrenia and neuronal degenerative diseases.
  

External links

Nomenclature
HGNC (Hugo)RTN4   14085
Cards
AtlasRTN4ID42182ch2p16
Entrez_Gene (NCBI)RTN4  57142  reticulon 4
GeneCards (Weizmann)RTN4
Ensembl (Hinxton)ENSG00000115310 [Gene_View]  chr2:55199327-55237470 [Contig_View]  RTN4 [Vega]
ICGC DataPortalENSG00000115310
AceView (NCBI)RTN4
Genatlas (Paris)RTN4
WikiGenes57142
SOURCE (Princeton)NM_007008 NM_020532 NM_153828 NM_207520 NM_207521
Genomic and cartography
GoldenPath (UCSC)RTN4  -  2p16.1   chr2:55199327-55237470 -  2p14-p13   [Description]    (hg19-Feb_2009)
EnsemblRTN4 - 2p14-p13 [CytoView]
Mapping of homologs : NCBIRTN4 [Mapview]
OMIM604475   
Gene and transcription
Genbank (Entrez)AB015639 AB020693 AB040462 AB040463 AB073351
RefSeq transcript (Entrez)NM_007008 NM_020532 NM_153828 NM_207520 NM_207521
RefSeq genomic (Entrez)AC_000134 NC_000002 NC_018913 NG_029037 NT_022184 NW_001838769 NW_004929300
Consensus coding sequences : CCDS (NCBI)RTN4
Cluster EST : UnigeneHs.637850 [ NCBI ]
CGAP (NCI)Hs.637850
Alternative Splicing : Fast-db (Paris)GSHG0017627
Alternative Splicing GalleryENSG00000115310
Gene ExpressionRTN4 [ NCBI-GEO ]     RTN4 [ SEEK ]   RTN4 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9NQC3 (Uniprot)
NextProtQ9NQC3  [Medical]
With graphics : InterProQ9NQC3
Splice isoforms : SwissVarQ9NQC3 (Swissvar)
Domaine pattern : Prosite (Expaxy)RETICULON (PS50845)   
Domains : Interpro (EBI)Reticulon   
Related proteins : CluSTrQ9NQC3
Domain families : Pfam (Sanger)Reticulon (PF02453)   
Domain families : Pfam (NCBI)pfam02453   
DMDM Disease mutations57142
Blocks (Seattle)Q9NQC3
PDB (SRS)2G31    2JV5   
PDB (PDBSum)2G31    2JV5   
PDB (IMB)2G31    2JV5   
PDB (RSDB)2G31    2JV5   
Human Protein AtlasENSG00000115310
Peptide AtlasQ9NQC3
HPRD07259
IPIIPI00021766   IPI00298289   IPI00219207   IPI00477663   IPI00478442   IPI00894213   IPI00873380   IPI01011809   IPI01025160   IPI00894099   IPI00414671   
Protein Interaction databases
DIP (DOE-UCLA)Q9NQC3
IntAct (EBI)Q9NQC3
FunCoupENSG00000115310
BioGRIDRTN4
IntegromeDBRTN4
STRING (EMBL)RTN4
Ontologies - Pathways
QuickGOQ9NQC3
Ontology : AmiGOangiogenesis  protein binding  intracellular  nuclear envelope  endoplasmic reticulum  endoplasmic reticulum  plasma membrane  apoptotic process  axonal fasciculation  cerebral cortex radial glia guided migration  integral component of endoplasmic reticulum membrane  negative regulation of cell growth  regulation of cell migration  negative regulation of axon extension  regulation of apoptotic process  cell projection  neuronal cell body  poly(A) RNA binding  neurotrophin TRK receptor signaling pathway  regulation of axonogenesis  negative regulation of axonogenesis  cardiac epithelial to mesenchymal transition  extracellular vesicular exosome  endoplasmic reticulum tubular network organization  regulation of branching morphogenesis of a nerve  
Ontology : EGO-EBIangiogenesis  protein binding  intracellular  nuclear envelope  endoplasmic reticulum  endoplasmic reticulum  plasma membrane  apoptotic process  axonal fasciculation  cerebral cortex radial glia guided migration  integral component of endoplasmic reticulum membrane  negative regulation of cell growth  regulation of cell migration  negative regulation of axon extension  regulation of apoptotic process  cell projection  neuronal cell body  poly(A) RNA binding  neurotrophin TRK receptor signaling pathway  regulation of axonogenesis  negative regulation of axonogenesis  cardiac epithelial to mesenchymal transition  extracellular vesicular exosome  endoplasmic reticulum tubular network organization  regulation of branching morphogenesis of a nerve  
REACTOMEQ9NQC3 [protein]
REACTOME PathwaysREACT_111102 Signal Transduction [pathway]
Protein Interaction DatabaseRTN4
Wikipedia pathwaysRTN4
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)RTN4
SNP (GeneSNP Utah)RTN4
SNP : HGBaseRTN4
Genetic variants : HAPMAPRTN4
1000_GenomesRTN4 
ICGC programENSG00000115310 
CONAN: Copy Number AnalysisRTN4 
Somatic Mutations in Cancer : COSMICRTN4 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
DECIPHER (Syndromes)2:55199327-55237470
Mutations and Diseases : HGMDRTN4
OMIM604475   
MedgenRTN4
GENETestsRTN4
Disease Genetic AssociationRTN4
Huge Navigator RTN4 [HugePedia]  RTN4 [HugeCancerGEM]
Genomic VariantsRTN4  RTN4 [DGVbeta]
Exome VariantRTN4
dbVarRTN4
ClinVarRTN4
snp3D : Map Gene to Disease57142
General knowledge
Homologs : HomoloGeneRTN4
Homology/Alignments : Family Browser (UCSC)RTN4
Phylogenetic Trees/Animal Genes : TreeFamRTN4
Chemical/Protein Interactions : CTD57142
Chemical/Pharm GKB GenePA34883
Clinical trialRTN4
Cancer Resource (Charite)ENSG00000115310
Other databases
Probes
Litterature
PubMed128 Pubmed reference(s) in Entrez
CoreMineRTN4
GoPubMedRTN4
iHOPRTN4

Bibliography

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Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F, Schwab ME
Nature. 2000 ; 403 (6768) : 434-439.
PMID 10667796
 
Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein.
GrandPrą© T, Nakamura F, Vartanian T, Strittmatter SM
Nature. 2000 ; 403 (6768) : 439-444.
PMID 10667797
 
Inhibitor of neurite outgrowth in humans.
Prinjha R, Moore SE, Vinson M, Blake S, Morrow R, Christie G, Michalovich D, Simmons DL, Walsh FS
Nature. 2000 ; 403 (6768) : 383-384.
PMID 10667780
 
A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity.
Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y
Oncogene. 2000 ; 19 (50) : 5736-5746.
PMID 11126360
 
Assignment of the human reticulon 4 gene (RTN4) to chromosome 2p14-->2p13 by radiation hybrid mapping.
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PMID 10773680
 
Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration.
Fournier AE, GrandPre T, Strittmatter SM
Nature. 2001 ; 409 (6818) : 341-346.
PMID 11201742
 
Link of a new type of apoptosis-inducing gene ASY/Nogo-B to human cancer.
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PMID 11494121
 
Nogo provides a molecular marker for diagnosis of amyotrophic lateral sclerosis.
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PMID 12270696
 
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Novak G, Kim D, Seeman P, Tallerico T
Brain research. Molecular brain research. 2002 ; 107 (2) : 183-189.
PMID 12425946
 
Axon regeneration in young adult mice lacking Nogo-A/B.
Kim JE, Li S, GrandPrą© T, Qiu D, Strittmatter SM
Neuron. 2003 ; 38 (2) : 187-199.
PMID 12718854
 
Genomic structure and functional characterisation of the promoters of human and mouse nogo/rtn4.
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PMID 12488097
 
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Journal of cellular physiology. 2003 ; 196 (2) : 312-318.
PMID 12811824
 
Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury.
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Neuron. 2003 ; 38 (2) : 201-211.
PMID 12718855
 
Multi-functional gene ASY/Nogo/RTN-X/RTN4: apoptosis, tumor suppression, and inhibition of neuronal regeneration.
Watari A, Yutsudo M
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PMID 12510146
 
Lack of enhanced spinal regeneration in Nogo-deficient mice.
Zheng B, Ho C, Li S, Keirstead H, Steward O, Tessier-Lavigne M
Neuron. 2003 ; 38 (2) : 213-224.
PMID 12718856
 
A new role for Nogo as a regulator of vascular remodeling.
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Nature medicine. 2004 ; 10 (4) : 382-388.
PMID 15034570
 
Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation.
He W, Lu Y, Qahwash I, Hu XY, Chang A, Yan R
Nature medicine. 2004 ; 10 (9) : 959-965.
PMID 15286784
 
Overexpression of human reticulon 3 (hRTN3) in astrocytoma.
Huang X, Yang H, Zhou Y, Liu J, Yin B, Peng X, Qiang B, Yuan J
Clinical neuropathology. 2004 ; 23 (1) : 1-7.
PMID 14986927
 
Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia.
Sinibaldi L, De Luca A, Bellacchio E, Conti E, Pasini A, Paloscia C, Spalletta G, Caltagirone C, Pizzuti A, Dallapiccola B
Human mutation. 2004 ; 24 (6) : 534-535.
PMID 15532024
 
Nogo-B is a new physiological substrate for MAPKAP-K2.
Rousseau S, Peggie M, Campbell DG, Nebreda AR, Cohen P
The Biochemical journal. 2005 ; 391 (Pt 2) : 433-440.
PMID 16095439
 
Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo.
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Proceedings of the National Academy of Sciences of the United States of America. 2005 ; 102 (4) : 1205-1210.
PMID 15647357
 
Human Nogo-C overexpression induces HEK293 cell apoptosis via a mechanism that involves JNK-c-Jun pathway.
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PMID 16905119
 
ER stress triggers apoptosis induced by Nogo-B/ASY overexpression.
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PMID 16687140
 
Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its ability to produce amyloid beta-protein.
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PMID 16965550
 
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PMID 17022955
 
The Nogo receptor complex: confining molecules to molecular mechanisms.
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Trends in molecular medicine. 2006 ; 12 (7) : 293-297.
PMID 16723274
 
Down-regulation of ASY/Nogo transcription associated with progression of adult T-cell leukemia/lymphoma.
Shimakage M, Inoue N, Ohshima K, Kawahara K, Oka T, Yasui K, Matsumoto K, Inoue H, Watari A, Higashiyama S, Yutsudo M
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PMID 16646068
 
A class of membrane proteins shaping the tubular endoplasmic reticulum.
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PMID 16469703
 
Reticulon proteins: emerging players in neurodegenerative diseases.
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PMID 16505974
 
Reticulon proteins: emerging players in neurodegenerative diseases.
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PMID 16505974
 
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Contributor(s)

Written01-2007Masuo Yutsudo

Citation

This paper should be referenced as such :
Yutsudo, M
RTN4 (reticulon 4)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(2):128-130.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/RTN4ID42182ch2p16.html

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indexed on : Sat Nov 8 16:31:40 CET 2014

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