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MCAM (melanoma cell adhesion molecule)

Written2012-02Guang-Jer Wu
Department of Microbiology, Immunology, Emory University School of Medicine, 1510, Clifton Rd NE, Atlanta, GA 30322, USA; Department of Bioscience Technology, Chung Yuan Christian University, 200 Chung Pei Rd, 32023 Taiwan, Republic of China

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Identity

Alias_symbol (synonym)MUC18
CD146
Other aliasMETCAM
Gicerin
HGNC (Hugo) MCAM
LocusID (NCBI) 4162
Atlas_Id 41314
Location 11q23.3  [Link to chromosome band 11q23]
Location_base_pair Starts at 119308524 and ends at 119317130 bp from pter ( according to hg19-Feb_2009)&lbsp;'njsp;[Mapping MCAM.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
MCAM (11q23.3) / C1D (2p14)MCAM (11q23.3) / CELF2 (10p14)MCAM (11q23.3) / FN1 (2q35)
MCAM (11q23.3) / SKP2 (5p13.2)MCAM (11q23.3) / SNAR-C4 (19q13.33)MCAM (11q23.3) / UBE2Q2P2 (15q25.2)

DNA/RNA

Description Human METCAM (huMETCAM), a CAM in the immunoglobulin-like gene superfamily, is an integral membrane glycoprotein. Alternative names for METCAM are MUC18 (Lehmann et al., 1987), CD146 (Anfosso et al., 2001), MCAM (Xie et al., 1997), MelCAM (Shih et al., 1994a), A32 (Shih et al., 1994b), and S-endo 1 (Bardin et al., 1996). To avoid confusion with mucins and to reflect its biological functions, we have renamed MUC18 as METCAM (metastasis CAM), which means an immunoglobulin-like CAM that affects or regulates metastasis, (Wu, 2005). METCAM/MUC18 gene is located on human chromosome 11q23.3.
Transcription The major transcript of the gene in most human epithelial cancer cell lines is about 3,3 kb (Wu et al., 2001a). A distinct short form resulting from alternative splicing of the gene of gicerin, the chicken homolog of METCAM, has been found (Taira et al., 1995). Though the expression of a short form of METCAM has been briefly mentioned in human melanoma cells (Lehmann et al., 1987), its function is not known since it is expressed at a much lower level than the major form in various cancer cell lines (Wu, unpublished observation). Interestingly, a truncated form with a deletion in some portion of the cytoplasmic domain has been found in a prostate cancer specimen X9479, a cell line derived from specimens of nasopharyngeal carcinomas and other cancers (Wu, unpublished observations). Further systematic search for the function of this minor form should be carried out.
Pseudogene METCAM/MUC18 may not have a pseudogene.

Protein

Note Human METCAM/MUC18 cDNA encodes 646 amino acids, about 115-150 kDa protein.
 
  HuMETCAM protein structure. SP stands for signal peptide sequence, V1, V2, C2, C2', C2'' for five Ig-like domains (each held by a disulfide bond) and X for one domain (without any disulfide bond) in the extracellular region, and TM for transmembrane domain. P stands for five potential phosphorylation sites (one for PKA, three for PKC, and one for CK2) in the cytoplasmic tail. The six conserved N-glycosylation sites are shown as wiggled lines in the extracellular domains of V1, between C2' and C2'', C2'', and X.
Description The huMETCAM has 646 amino acids that include a N-terminal extra-cellular domain of 558 amino acids, which has 28 amino acids characteristics of a signal peptide sequence at its N-terminus, a transmembrane domain of 24 amino acids (amino acids 559-583), and a cytoplasmic domain of 64 amino acids at the C-terminus. HuMETCAM has eight putative N-glycosylation sites (Asn-X-Ser/Thr), of which six are conserved, and are heavily glycosylated and sialylated resulting in an apparent molecular weight of 113000-150000. The extra-cellular domain of the protein comprises five immunoglobulin-like domains (V-V-C2-C2-C2) (Lehmann et al., 1987; Wu et al., 2001a; Wu, 2005) and an X domain (Wu et al., 2001a; Wu, 2005). The cytoplasmic tail contains peptide sequences that will potentially be phosphorylated by protein kinase A (PKA), protein kinase C (PKC), and casein kinase 2 (CK 2) (Lehmann et al., 1987; Wu et al., 2001a; Wu, 2005). My lab has also cloned and sequenced the mouse METCAM (moMETCAM) cDNA, which contains 648 amino acids with a 76,2% identity with huMETCAM, suggesting that moMETCAM is likely to have biochemical properties and biological functions similar to the human counter part (Yang et al., 2001; Wu, 2005). The structure of the huMETCAM protein is depicted in figure above, suggesting that METCAM, similar to most CAMs, plays an active role in mediating cell-cell and cell-extracellular interactions, crosstalk with many intracellular signaling pathways, and modulating the social behaviors of cells (Cavallaro and Christofori, 2004; Wu, 2005). Recent work supports an emerging novel function of METCAM in tumor angiogenesis and perhaps it plays an important role in the metastasis of tumor cells (Wu, 2010; Wu, 2012).
Expression HuMETCAM is expressed in a limited number of normal tissues, such as hair follicular cells, smooth muscle cells, endothelial cells, cerebellum, normal mammary epithelial cells, basal cells of the lung, activated T cells, intermediate trophoblast (Shih, 1999), and normal nasopharyngeal epithelial cells (Lin et al., 2012).
Localisation HuMETCAM is a cytoplasmic membrane protein. Most of the protein is located on the cell membrane in normal tissues. However, increasing presence of the protein in the cytoplasm appears to be related to the higher pathological grades and malignant cancers of prostate and breast, and melanoma and nasopharyngeal carcinoma (Wu et al., 2001b).
Function Similar to other cell adhesion molecules (CAMs), METCAM/MUC18 does not merely act as a molecular glue to hold together homotypic cells in a specific tissue or to facilitate interactions of heterotypic cells; It also actively governs the social behaviors of cells by affecting the adhesion status of cells and modulating cell signaling (Cavallaro and Christofori, 2004). It controls cell motility and invasiveness by mediating the remodeling of cytoskeleton (Cavallaro and Christofori, 2004). It also actively mediates the cell-to-cell and cell-to-extracellular matrix interactions to allow cells to constantly respond to physiological fluctuations and to alter/remodel the surrounding microenvironment for survival (Chambers et al., 2002). It does so by crosstalk with cellular surface growth factor receptors, which interact with growth factors that may be secreted from stromal cells or released from circulation and embedded in the extracellular matrix (Chambers et al., 2002; Cavallaro and Christofori, 2004). Thus an altered expression of METCAM/MUC18 affects the motility and invasiveness of many epithelial tumor cells in vitro and metastasis in vivo (Chambers et al., 2002; Cavallaro and Christofori, 2004; Wu, 2005). METCAM/MUC18 may also play an important role in the favorable soil that provides a proper microenvironment at a suitable period to awaken the dormant metastatic tumor cells to enter into an aggressive growth phase. Evidence have been documented that aberrant expression of huMETCAM/MUC18 actually affects the motility and invasiveness of many tumor cells in vitro and metastasis in vivo. Thus HuMETCAM/MUC18 plays an important role in promoting the malignant progression of many cancer types (Cavallaro and Christofori, 2004; Wu, 2005).
Homology Human METCAM/MUC18 protein shares high homology with the mouse METCAM/MUC18 (Wu et al., 2001a; Yang et al., 2001) and other Ig-like CAMs, especially the NCAMs (Lehmann et al., 1987).

Mutations

Note Several point mutations have been found in huMETCAM/MUC18 protein from human cancers (Wu et al., 2001a).

Implicated in

Note
  
Entity Various cancers
Note The protein is overly expressed in most (67%) malignant melanoma cells (Lehmann et al., 1987), and in most (more than 80%) pre-malignant prostate epithelial cells (PIN), high-grade prostatic carcinoma cells, and metastatic lesions (Wu et al., 2001b; Wu, 2004). HuMETCAM is also expressed in other cancers, such as gestational trophoblastic tumors, leiomyosarcoma, angiosarcoma, haemangioma, Kaposi's sarcoma, schwannoma, some lung squamous and small cell carcinomas, some breast cancer, some neuroblastoma (Shih, 1999), and also nasopharyngeal carcinoma (Lin et al., 2012) and ovarian cancer (Wu et al., 2012).
  
  
Entity Breast cancer
Note Over-expression of huMETCAM has been shown to promote tumorigenesis of four breast cancer cell lines in athymic nude mice and perhaps the malignant progression of breast cancer cells (Zeng et al., 2011; Zeng et al., 2012).
Prognosis Over-expression of huMETCAM/MUC18 has been implicated in a poor prognosis of breast cancer.
  
  
Entity Prostate cancer
Note Over-expression of huMETCAM has been shown to promote tumorigenesis and metastasis of human prostate cancer LNCaP cells in athymic nude mice (Wu et al., 2001a; Wu et al., 2001b; Wu, 2004; Wu et al., 2004; Wu et al., 2011).
Disease Human prostate cancer (Wu et al., 2001a; Wu et al., 2001b; Wu, 2004; Wu et al., 2004; Wu et al., 2011) and the TRAMP models (Wu et al., 2005).
Prognosis Over-expression of huMETCAM/MUC18 has been implicated in a poor prognosis of prostate cancer (Wu et al., 2001a; Wu et al., 2001b, Wu, 2004).
Oncogenesis METCAM/MUC18 promotes the oncogenesis of human prostate cancer cells (Wu et al., 2001a; Wu et al., 2001b; Wu, 2004; Wu et al., 2004; Wu et al., 2011).
  
  
EntityMelanoma
Note Over-expression of huMETCAM has been shown to promote metastasis, but not the tumorigenesis, of human melanoma (Xie et al., 1997; Schlagbauer-Wadl et al., 1999) and mouse melanoma cells (Yang et al., 2001; Wu et al., 2008) in immunodeficent nude mice.
Prognosis Over-expression of huMETCAM/MUC18 has been implicated in a poor prognosis of melanoma (Lehmann et al., 1987; Shih, 1999).
Oncogenesis METCAM does not appear to promote the oncogenesis of human and most melanoma cells (Wu et al., 2008).
  

Bibliography

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MUC18, a marker of tumor progression in human melanoma, shows sequence similarity to the neural cell adhesion molecules of the immunoglobulin superfamily.
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Decreased expression of METCAM/MUC18 correlates with the appearance of, but its increased expression with metastasis of nasopharyngeal carcinoma.
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2012, (submitted).
 
Influence of MUC18/MCAM/CD146 expression on human melanoma growth and metastasis in SCID mice.
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Expression and functional analysis of a novel isoform of gicerin, an immunoglobulin superfamily cell adhesion molecule.
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Enforced expression of MCAM/MUC18 increases in vitro motility and invasiveness and in vivo metastasis of two mouse melanoma K1735 sublines in a syngeneic mouse model.
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Mol Cancer Res. 2008 Nov;6(11):1666-77.
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Ectopical expression of human MUC18 increases metastasis of human prostate cancer cells.
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Gene. 2004 Mar 3;327(2):201-13.
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METCAM/MUC18 over-expression in human ovarian cancer tissues and metastatic lesions is associated with clinical progression.
Wu GJ, Son ES, Dickerson EB, McDonald JF, Cohen C, Sanjay L, Wu MWH.
2012, (submitted).
 
Expression of a human cell adhesion molecule, MUC18, in prostate cancer cell lines and tissues.
Wu GJ, Varma VA, Wu MW, Wang SW, Qu P, Yang H, Petros JA, Lim SD, Amin MB.
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Enforced expression of METCAM/MUC18 increases tumorigenesis of human prostate cancer LNCaP cells in nude mice.
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Dual roles of METCAM in the progression of different cancers.
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Citation

This paper should be referenced as such :
Wu, GJ
MCAM (melanoma cell adhesion molecule)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(7):476-479.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MCAMID41314ch11q23.html


External links

Nomenclature
HGNC (Hugo)MCAM   6934
Cards
AtlasMCAMID41314ch11q23
Entrez_Gene (NCBI)MCAM  4162  melanoma cell adhesion molecule
AliasesCD146; MUC18
GeneCards (Weizmann)MCAM
Ensembl hg19 (Hinxton)ENSG00000076706 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000076706 [Gene_View]  chr11:119308524-119317130 [Contig_View]  MCAM [Vega]
ICGC DataPortalENSG00000076706
TCGA cBioPortalMCAM
AceView (NCBI)MCAM
Genatlas (Paris)MCAM
WikiGenes4162
SOURCE (Princeton)MCAM
Genetics Home Reference (NIH)MCAM
Genomic and cartography
GoldenPath hg38 (UCSC)MCAM  -     chr11:119308524-119317130 -  11q23.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MCAM  -     11q23.3   [Description]    (hg19-Feb_2009)
EnsemblMCAM - 11q23.3 [CytoView hg19]  MCAM - 11q23.3 [CytoView hg38]
Mapping of homologs : NCBIMCAM [Mapview hg19]  MCAM [Mapview hg38]
OMIM155735   
Gene and transcription
Genbank (Entrez)AB209925 AF089868 AJ297452 AK126303 AK128335
RefSeq transcript (Entrez)NM_006500
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)MCAM
Cluster EST : UnigeneHs.599039 [ NCBI ]
CGAP (NCI)Hs.599039
Alternative Splicing GalleryENSG00000076706
Gene ExpressionMCAM [ NCBI-GEO ]   MCAM [ EBI - ARRAY_EXPRESS ]   MCAM [ SEEK ]   MCAM [ MEM ]
Gene Expression Viewer (FireBrowse)MCAM [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4162
GTEX Portal (Tissue expression)MCAM
Human Protein AtlasENSG00000076706-MCAM [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP43121   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP43121  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP43121
Splice isoforms : SwissVarP43121
PhosPhoSitePlusP43121
Domaine pattern : Prosite (Expaxy)IG_LIKE (PS50835)   
Domains : Interpro (EBI)CD80_C2-set    Ig-like_dom    Ig-like_fold    Ig_sub    Ig_sub2    Ig_V-set    Immunoglobulin   
Domain families : Pfam (Sanger)C2-set_2 (PF08205)    ig (PF00047)    V-set (PF07686)   
Domain families : Pfam (NCBI)pfam08205    pfam00047    pfam07686   
Domain families : Smart (EMBL)IG (SM00409)  IGc2 (SM00408)  
Conserved Domain (NCBI)MCAM
DMDM Disease mutations4162
Blocks (Seattle)MCAM
SuperfamilyP43121
Human Protein Atlas [tissue]ENSG00000076706-MCAM [tissue]
Peptide AtlasP43121
HPRD01120
IPIIPI00016334   IPI00445227   IPI01014208   IPI00978774   
Protein Interaction databases
DIP (DOE-UCLA)P43121
IntAct (EBI)P43121
FunCoupENSG00000076706
BioGRIDMCAM
STRING (EMBL)MCAM
ZODIACMCAM
Ontologies - Pathways
QuickGOP43121
Ontology : AmiGOangiogenesis  glomerular filtration  extracellular space  nucleus  plasma membrane  focal adhesion  cell adhesion  anatomical structure morphogenesis  external side of plasma membrane  integral component of membrane  positive regulation of cell migration  vascular wound healing  
Ontology : EGO-EBIangiogenesis  glomerular filtration  extracellular space  nucleus  plasma membrane  focal adhesion  cell adhesion  anatomical structure morphogenesis  external side of plasma membrane  integral component of membrane  positive regulation of cell migration  vascular wound healing  
NDEx NetworkMCAM
Atlas of Cancer Signalling NetworkMCAM
Wikipedia pathwaysMCAM
Orthology - Evolution
OrthoDB4162
GeneTree (enSembl)ENSG00000076706
Phylogenetic Trees/Animal Genes : TreeFamMCAM
HOVERGENP43121
HOGENOMP43121
Homologs : HomoloGeneMCAM
Homology/Alignments : Family Browser (UCSC)MCAM
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMCAM [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MCAM
dbVarMCAM
ClinVarMCAM
1000_GenomesMCAM 
Exome Variant ServerMCAM
ExAC (Exome Aggregation Consortium)ENSG00000076706
GNOMAD BrowserENSG00000076706
Genetic variants : HAPMAP4162
Genomic Variants (DGV)MCAM [DGVbeta]
DECIPHERMCAM [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisMCAM 
Mutations
ICGC Data PortalMCAM 
TCGA Data PortalMCAM 
Broad Tumor PortalMCAM
OASIS PortalMCAM [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMCAM  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDMCAM
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
BioMutasearch MCAM
DgiDB (Drug Gene Interaction Database)MCAM
DoCM (Curated mutations)MCAM (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MCAM (select a term)
intoGenMCAM
NCG5 (London)MCAM
Cancer3DMCAM(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM155735   
Orphanet
MedgenMCAM
Genetic Testing Registry MCAM
NextProtP43121 [Medical]
TSGene4162
GENETestsMCAM
Target ValidationMCAM
Huge Navigator MCAM [HugePedia]
snp3D : Map Gene to Disease4162
BioCentury BCIQMCAM
ClinGenMCAM
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4162
Chemical/Pharm GKB GenePA30678
Clinical trialMCAM
Miscellaneous
canSAR (ICR)MCAM (select the gene name)
Probes
Litterature
PubMed144 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMCAM
EVEXMCAM
GoPubMedMCAM
iHOPMCAM
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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