MCAM (melanoma cell adhesion molecule)

2012-02-01   Guang-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





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.


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function is not known since it is expressed at a much lower level than the major form in various cancer cell lines (Wu, unpublished observation).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prostate cancer specimen X9479, a cell line derived from specimens of nasopharyngeal carcinomas and other cancers (Wu, unpublished observations).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.


METCAM/MUC18 may not have a pseudogene.



Human METCAM/MUC18 cDNA encodes 646 amino acids, about 115-150 kDa protein.
Atlas Image
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.


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).


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).


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).


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).


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).



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

Implicated in

Entity name
Various cancers
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, Kaposis 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 name
Breast cancer
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).
Over-expression of huMETCAM/MUC18 has been implicated in a poor prognosis of breast cancer.
Entity name
Prostate cancer
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).
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).
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).
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).
Entity name
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.
Over-expression of huMETCAM/MUC18 has been implicated in a poor prognosis of melanoma (Lehmann et al., 1987; Shih, 1999).
METCAM does not appear to promote the oncogenesis of human and most melanoma cells (Wu et al., 2008).


Pubmed IDLast YearTitleAuthors
110360772001Outside-in signaling pathway linked to CD146 engagement in human endothelial cells.Anfosso F et al
89885351996S-Endo 1, a pan-endothelial monoclonal antibody recognizing a novel human endothelial antigen.Bardin N et al
149643082004Cell adhesion and signalling by cadherins and Ig-CAMs in cancer.Cavallaro U et al
121543492002Dissemination and growth of cancer cells in metastatic sites.Chambers AF et al
26023811989MUC18, a marker of tumor progression in human melanoma, shows sequence similarity to the neural cell adhesion molecules of the immunoglobulin superfamily.Lehmann JM et al
103621441999Influence of MUC18/MCAM/CD146 expression on human melanoma growth and metastasis in SCID mice.Schlagbauer-Wadl H et al
81626021994Isolation and functional characterization of the A32 melanoma-associated antigen.Shih IM et al
104514811999The role of CD146 (Mel-CAM) in biology and pathology.Shih IM et al
74993881995Expression and functional analysis of a novel isoform of gicerin, an immunoglobulin superfamily cell adhesion molecule.Taira E et al
190108152008Enforced 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.Wu GJ et al
149807172004Ectopical expression of human MUC18 increases metastasis of human prostate cancer cells.Wu GJ et al
115363112001Expression of a human cell adhesion molecule, MUC18, in prostate cancer cell lines and tissues.Wu GJ et al
213346702011Enforced expression of METCAM/MUC18 increases tumorigenesis of human prostate cancer LNCaP cells in nude mice.Wu GJ et al
91871351997Expression of MCAM/MUC18 by human melanoma cells leads to increased tumor growth and metastasis.Xie S et al
112550162001Isolation and characterization of mouse MUC18 cDNA gene, and correlation of MUC18 expression in mouse melanoma cell lines with metastatic ability.Yang H et al
220570132012METCAM/MUC18 augments migration, invasion, and tumorigenicity of human breast cancer SK-BR-3 cells.Zeng G et al
214500882011Up-regulation of METCAM/MUC18 promotes motility, invasion, and tumorigenesis of human breast cancer cells.Zeng GF et al

Other Information

Locus ID:

NCBI: 4162
MIM: 155735
HGNC: 6934
Ensembl: ENSG00000076706


dbSNP: 4162
ClinVar: 4162
TCGA: ENSG00000076706


Gene IDTranscript IDUniprot

Expression (GTEx)


Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
201277982010In vitro high-capacity assay to quantify the clonal heterogeneity in trilineage potential of mesenchymal stem cells reveals a complex hierarchy of lineage commitment.140
214152672011CD146 expression on primary nonhematopoietic bone marrow stem cells is correlated with in situ localization.129
178729082007Co-expression of two perivascular cell markers isolates mesenchymal stem-like cells from human endometrium.125
232664262013CD146, a multi-functional molecule beyond adhesion.77
191239252009CD146 expression is associated with a poor prognosis in human breast tumors and with enhanced motility in breast cancer cell lines.53
234120952013Perivascular support of human hematopoietic stem/progenitor cells.53
227188412012CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis.51
179820572007Dual role of melanoma cell adhesion molecule (MCAM)/CD146 in lymphocyte endothelium interaction: MCAM/CD146 promotes rolling via microvilli induction in lymphocyte and is an endothelial adhesion receptor.39
192290702009CD146 and its soluble form regulate monocyte transendothelial migration.39
251352962014VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells.38


Guang-Jer Wu

MCAM (melanoma cell adhesion molecule)

Atlas Genet Cytogenet Oncol Haematol. 2012-02-01

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