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NRCAM (neuronal cell adhesion molecule)

Identity

Other namesBravo
Nr-CAM
HGNC (Hugo) NRCAM
Location 7q31.1
Location_base_pair Starts at 107575318 and ends at 107884062 bp from pter ( according to hg18-Mar_2006)  [Mapping]

DNA/RNA

 
  Cartoon of the distribution of NrCAM exons, including those used in most transcripts (open boxes) and those that are alternatively spliced (filled boxes). Most exons are conserved in human, mouse and rat. Exons 1b and 33 have not been identified in humans. The candidate alternatively transcribed exons produce the shorter rat and human isoforms are shown in the bottom two rows. (Rows 3-8) NrCAM clones (Nc)1, 3, 6, 7, 14, 17 that represent splice variant isoforms identified in rat brain cDNAs. (Rows 9-10) Shorter NrCAM gene product expressed isoforms that are identified from ESTs in rat and human databases (from Ishiguro et al., 2006).
Description The NrCAM gene is about 316 kb in length, consisting of 34 exons.
Transcription NrCAM is transcribed from a single gene and the mRNA may be alternatively processed into multiple species (Grumet et al., 1991). Different transcripts of NRCAM are produced by alternative splicing of exons 10, 19 and 27-29.
There are three main alternative spliced mRNA according to Entrez: variant A - NM_001037132.1, variant B - NM_005010.3, variant C - NM_001037133.1.

Protein

 
  Cartoon of NrCAM's structure with fibronectin, immunoglobulin, transmembrane, and intracellular (C-terminal) domains indicated. Arrows indicate sites where splice variants encode additional inserted additional amino acids. These NrCAM structures are conserved in human, mouse, and rat. (from Ishiguro et al., 2006).
Description NrCAM is a cell surface protein of the immunoglobulin superfamily, L1/neurofascin/NgCAM subgroup. The molecule is 200-220kDa transmembrane protein, which contains 5 fibronectin type-III domains, 6 Ig-like C2-type (immunoglobulin-like) domains in the extracellular region and a highly conserved cytoplasmic tail. (Grumet et al., 1991; Kayyem et al., 1992; Lane et al., 1996).
Human NrCAM has few alternatively spliced regions: AE19 adds 19 amino acids to the region between Ig domain 2 and 3; AE10 lies clearly between Ig domain 6 and the beginning of the Fn repeats; AE10K2 encompasses part of the G strand of Ig 5 and most of the A strand of Ig 6; AE12 affects the G strand of Fn III domain 4; AE93 corresponds to the entire Fn type III domain (Grumet et al.,1991; Lane et al., 1996; Wang et al., 1998).
Expression Central and peripheral nervous system, and other tissues, endothelial cells, and certain tumor cell lines and human cancers including pancreatic cancer, melanoma, renal and colon carcinoma, adrenal gland, placenta, thyroid and testis (Wang et al., 1998; Glienke et al, 2000; Dhodapkar et al., 2001; Aitkenhead et al, 2002; Conacci-Sorrell et al., 2002).
Nervous system: NrCAM is expressed in structures in the developing brain. In the floor plate NrCAM has been implicated in axonal guidance trough interaction with TAG-1/axonin-1 (Lustig et al., 2001). Moreover, NrCAM induces neurite outgrowth from dorsal root ganglia neurons. It also operates as a receptor for several different neuronal recognition molecules. NrCAM protein promotes directional signaling during nervous system development in several different regions as the spinal cord, the visual system, and the cerebellum (Lustig et al., 2001; Hutcheson et al., 2004).
Localisation Various cell compartments: external side of plasma membrane, integral to plasma membrane, neuron projection, cytoplasm, nucleus.
Function NrCAM is engaged in such biological processes as axonal fasciculation, cell-cell adhesion, central nervous system development, clustering of voltage-gated sodium channels, neuron migration, positive regulation of neuron differentiation, regulation of axon extension, and synaptogenesis. It also may play a role in the molecular assembly of the nodes of Ranvier. NrCAM effects are also linked with different recognition processes and signal transduction pathways regulating cell differentiation, proliferation, or migration (Gumbiner, 1996; Cavallaro and Christofori, 2004).
Homology - NRCAM, neuronal cell adhesion molecule, Homo sapiens
- NRCAM, neuronal cell adhesion molecule, Bos taurus
- Nrcam, neuron-glia-CAM-related cell adhesion molecule, Mus musculus
- Nrcam, neuron-glia-CAM-related cell adhesion molecule, Rattus norvegicus
- NRCAM, neuronal cell adhesion molecule, Gallus gallus
- si:dkey-240a12.1, si:dkey-240a12.1, Danio rerio
- Nrg, Neuroglian, Drosophila melanogaster
- AgaP_AGAP000720, AGAP000720-PA, Anopheles gambiae
- lad-2, L1 CAM ADhesion molecule homolog, Caenorhabditis elegans
- NRCAM, neuronal cell adhesion molecule, Pan troglodytes
- LOC475881, similar to Neuronal cell adhesion m..., Canis lupus familiaris.

Mutations

Somatic According to UniProt database there are two known somatic mutations of NrCAM gene, both related to breast cancer (Sjoblom et al., 2006). First mutation results in amino-acids change from medium size and polar His to hydrophobic Pro (H1093P) in the Fn-III 5 domain, and in consequence missing in isoform 3 and 5 NrCAM protein. Second leads to another amino-acids substitution G1116V in the Fn-III 5 domain and effects in missing of 3 and 4 isoforms.

Implicated in

Entity Brain tumor
Disease NrCAM is over-expressed in high-grade astrocytoma, glioma and glioblastoma tumor tissues. High expression of NrCAM was also observed in cell lines derived from tumors mentioned above. Low levels of NrCAM expression were observed in neuroblastoma and meningioma. Northern blot analysis showed an alternatively spliced mRNA of 1.4 kb that could translate into a small variant of the NRCAM protein, which may be tumor-specific. Analysis of DNA from brain tumor cell lines showed that over-expression of NrCAM was not due to gene amplification. The results suggest that NrCAM is over-expressed in malignant brain tumors and can serve as a novel marker for brain tumor detection and perhaps therapy (Sehgal et al., 1998).
  
Entity Colon cancer
Disease NrCAM expression is induced by beta-catenin and plakoglobin in complex with LEF/TCF through activation the NrCAM promoter where several LEF/TCF binding sites are localized. Excessive activation of beta-catenin signaling is characteristic for colon cancer. Significant expression of NrCAM was demonstrated in the human colon cancer cell lines, and more importantly in colon carcinoma tissue samples but not in normal colon. The results indicate that NrCAM, as a target gene of the beta-catenin-TCF/LEF-1 pathway, may play a key role in the colon cancer tumorigenesis, probably by promoting cell growth and motility (Conacci-Sorrell at al., 2002).
  
Entity Melanoma
Disease Melanoma cell lines from advanced stages of human melanoma, which express high levels of NrCAM, stimulate cell growth, enhance motility, induce transformation, and produce rapidly growing tumors in nude mice, while those lacking NrCAM do not. NrCAM was found in complex with alpha4 integrin and beta1 integrin in melanoma cells, indicating that it can mediate heterophilic adhesion with extracellular matrix receptors. Suppression of NrCAM levels by small interfering RNA (siRNA) inhibits the adhesive and tumorigenic capacities of these cells, and implies that NrCAM expression is necessary for these cellular processes in melanoma cells. (Conacci-Sorrell et al., 2002 and 2005).
  
Entity Pancreatic carcinoma
Disease NrCAM is expressed by nonneuronal elements of human pancreas and is dysregulated in various stages of pancreatic cancer. In normal tissue, NrCAM is expressed predominantly on the surface of acinal cells, and very weekly on normal ducts. In most poorly differentiated tumors as well as human pancreatic adenocarcinoma cell lines decreased or no expression of the protein is seen, whereas the well and moderately differentiated carcinomas show elevated expression. The data indicate expression of NrCAM in normal pancreas and loss in pancreatic adenocarcinoma. Taken together, this differential tissue- and cell-specific regulation of NrCAM expression suggests that this molecule may be involved in the pathogenesis and invasive/metastatic behavior of pancreatic cancers (Dhodapkar et al., 2001).
  
Entity Papillary thyroid carcinoma
Disease NrCAM is over-expressed in papillary thyroid carcinoma (PTC) on both gene and protein levels. The upregulation of NrCAM gene is not related to the primary tumor stage (TNM) and size (Gorka et al., 2007). NrCAM gene over-expression in papillary thyroid carcinoma was also shown by DNA microarrays study (Jarzab et al., 2005; Delys et al., 2007). Moreover, artificially raised expression of RET/PTC1) in normal human thyrocytes, directly induces many inflammatory and tumor invasion genes including the NrCAM (Borello et al., 2005). NrCAM induction and over-expression in PTC cells regardless of the primary tumor stage suggests that this is an early event during PTC development.
  
Entity Autism
Disease Results from various genomic screens provide evidence for an autism susceptibility region on chromosome 7q31, which contains NRCAM gene.
According to Hutcheson et al. (2004) none of the individual polymorphisms in or surrounding NRCAM demonstrated evidence for allelic association to autism. The distinct results have been reported by Bonora et al. in 2005. Screening for mutations in unrelated individuals with autism led to identification of polymorphisms in the promoter and untranslated region of NRCAM. Results suggest that alterations in expression of NRCAM gene may be linked to autism susceptibility, and association was more significant when considering the haplotype transmission (Bonora et al., 2005).
  

External links

Nomenclature
HGNC (Hugo)NRCAM   7994
Entrez_Gene (NCBI)NRCAM  4897  neuronal cell adhesion molecule
Cards
AtlasNRCAMID41578ch7q31
GeneCards (Weizmann)NRCAM
Ensembl (Hinxton)ENSG00000091129 [Gene_View]  NRCAM [Vega]
AceView (NCBI)NRCAM
Genatlas (Paris)NRCAM
euGene (Indiana)4897
SOURCE (Stanford)NM_001037132 NM_001037133 NM_005010
Gene Expression (Array Express) ENSG00000091129
Genomic and cartography
GoldenPath (UCSC)NRCAM  -  7q31.1   chr7:107575318-107884062 -  7q31.1-q31.2   [Description]    (hg18-Mar_2006)
EnsemblNRCAM - 7q31.1-q31.2 [CytoView]
Mapping of homologs : NCBINRCAM [Mapview]
OMIM601581   
Gene and transcription
Gene : Genbank (Entrez)AB002341 AI031622 AJ001054 AJ001057 AK092330
Reference sequence (RefSeq transcript) :SRSNM_001037132 NM_001037133 NM_005010
Reference transcript : EntrezNM_001037132 NM_001037133 NM_005010
RefSeq genomic : SRSAC_000050 AC_000068 AC_000139 NC_000007 NT_007933 NT_079596 NW_001839071 NW_923640
RefSeq genomic : EntrezAC_000050 AC_000068 AC_000139 NC_000007 NT_007933 NT_079596 NW_001839071 NW_923640
Consensus coding sequences : CCDS NCBINRCAM
Cluster EST : UnigeneHs.21422 [ SRS ] Hs.21422 [ NCBI ]
Alternative Splicing : Fast-db (Paris)10794
Protein : pattern, domain, 3D structure
Protein : UniProt/SwissProtQ92823 (SRS) Q92823 (Expasy) Q92823 (Uniprot)
With graphics : InterProQ92823
Splice isoforms : VarSplice FASTAQ92823(VarSplice FASTA)
Domaine pattern : Prosite (SRS)FN3 (PS50853)    IG_LIKE (PS50835)    IG_MHC (PS00290)   
Domain pattern : Prosite (Expaxy)FN3 (PS50853)    IG_LIKE (PS50835)    IG_MHC (PS00290)   
Domains : Interpro (SRS)Fibronectin_typ-III-like_fold    FN_III    Ig-like    Ig-like_fold    Ig/MHC_CS    Ig_I-set    Ig_sub    Ig_sub2   
Domains : Interpro (EBI)Fibronectin_typ-III-like_fold    FN_III    Ig-like    Ig-like_fold    Ig/MHC_CS    Ig_I-set    Ig_sub    Ig_sub2   
Related proteins : CluSTrQ92823
Domain families : Pfam SRSfn3 (PF00041)    I-set (PF07679)   
Domain families : Pfam Sangerfn3 (PF00041)    I-set (PF07679)   
Domain families : Pfam NCBIpfam00041    pfam07679   
Domain families : Smart EMBLFN3 (SM00060)  IG (SM00409)  IGc2 (SM00408)  
Blocks (Seattle)Q92823
Crystal structure of protein : PDB SRS1UEN    1UEY   
Crystal structure of protein : PDBSum1UEN    1UEY   
Crystal structure of protein : IMB1UEN    1UEY   
Crystal structure of protein : PDB RSDB1UEN    1UEY   
HPRD07207
Protein Interaction databases
DIP (DOE-UCLA)Q92823
IntAct (EBI)Q92823
Polymorphism : SNP, mutations, diseases
Single Nucleotide Polymorphism (SNP) : dbSNP NCBINRCAM
SNP : GeneSNP UtahNRCAM
SNP : HGBaseNRCAM
Genetic variants : HAPMAPNRCAM
Somatic Mutations in Cancer : COSMICNRCAM 
Mutations and Diseases : HGMDNRCAM
Hereditary diseases : OMIM601581   
Hereditary diseases : GENETests601581   
Diseases : Genetic AssociationNRCAM
General knowledge
Homologs : HomoloGeneNRCAM
Homology/Alignments : Family Browser UCSCNRCAM
Phylogenetic Trees/Animal Genes : TreeFamNRCAM
Chemical/Protein Interactions : CTD4897
Keywords Ontology : AmiGOneuron migration  protein binding  plasma membrane  integral to plasma membrane  axonal fasciculation  synapse assembly  central nervous system development  external side of plasma membrane  cell-cell adhesion  ankyrin binding  regulation of axon extension  neuron projection  clustering of voltage-gated sodium channels  positive regulation of neuron differentiation  
Keywords Ontology : EGO-EBIneuron migration  protein binding  plasma membrane  integral to plasma membrane  axonal fasciculation  synapse assembly  central nervous system development  external side of plasma membrane  cell-cell adhesion  ankyrin binding  regulation of axon extension  neuron projection  clustering of voltage-gated sodium channels  positive regulation of neuron differentiation  
Pathways : BIOCARTA
Pathways : KEGGCell adhesion molecules (CAMs)
Other databases
Probes
Probes : ImagenesNRCAM Related clones (RZPD - Berlin)
Literature
PubMed30 Pubmed reference(s) in Entrez
PubGeneNRCAM

Bibliography

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Differential gene expression by endothelial cells in distinct angiogenic states.
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Identification of endothelial cell genes expressed in an in vitro model of angiogenesis: induction of ESM-1, (beta)ig-h3, and NrCAM.
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Nr-CAM is a target gene of the beta-catenin/LEF-1 pathway in melanoma and colon cancer and its expression enhances motility and confers tumorigenesis.
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The shed ectodomain of Nr-CAM stimulates cell proliferation and motility, and confers cell transformation.
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NrCAM in addiction vulnerability: positional cloning, drug-regulation, haplotype-specific expression, and altered drug reward in knockout mice.
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Contributor(s)

Written02-2009Justyna Janik, Barbara Czarnocka
Department of Biochemistry and Molecular Biology, Medical Centre of Postgraduate Education, ul. Marymoncka 99/103, 01-813 Warsaw, Poland

Citation

This paper should be referenced as such :
Janik J, Czarnocka B . NRCAM (neuronal cell adhesion molecule). Atlas Genet Cytogenet Oncol Haematol. February 2009 .
URL : http://AtlasGeneticsOncology.org/Genes/NRCAMID41578ch7q31.html

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