Download Gene Section MCAM (melanoma cell adhesion molecule) Atlas of Genetics and Cytogenetics

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Gene Section
Review
MCAM (melanoma cell adhesion molecule)
Guang-Jer Wu
Department of Microbiology and 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 (GJW)
Published in Atlas Database: February 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/MCAMID41314ch11q23.html
DOI: 10.4267/2042/47418
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
form in various cancer cell lines (Wu, unpublished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carcinomas and other cancers (Wu, unpublished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.
Identity
Other names: CD146, METCAM, MUC18, Gicerin
HGNC (Hugo): MCAM
Location: 11q23.3
DNA/RNA
Description
Pseudogene
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.
METCAM/MUC18 may not have a pseudogene.
Protein
Note
Human METCAM/MUC18 cDNA encodes 646 amino
acids, about 115-150 kDa protein.
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 Cterminus. HuMETCAM has eight putative Nglycosylation sites (Asn-X-Ser/Thr), of which six are
conserved, and are heavily glycosylated and sialylated
resulting in an apparent molecular weight of 113000150000.The extra-cellular domain of the protein
comprises five immunoglobulin-like domains (V-VC2-C2-C2) (Lehmann et al., 1987; Wu et al., 2001a;
Wu, 2005) and an X domain (Wu et al., 2001a; Wu,
2005).
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
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
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MCAM (melanoma cell adhesion molecule)
Wu GJ
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 Nglycosylation sites are shown as wiggled lines in the extracellular domains of V1, between C2' and C2'', C2'', and X.
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).
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-toextracellular 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).
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).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
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MCAM (melanoma cell adhesion molecule)
Wu GJ
Homology
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).
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).
Melanoma
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).
Mutations
Note
Several point mutations have been found in
huMETCAM/MUC18 protein from human cancers
(Wu et al., 2001a).
Implicated in
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).
References
Lehmann JM, Riethmüller G, Johnson JP. MUC18, a marker of
tumor progression in human melanoma, shows sequence
similarity to the neural cell adhesion molecules of the
immunoglobulin superfamily. Proc Natl Acad Sci U S A. 1989
Dec;86(24):9891-5
Shih IM, Elder DE, Hsu MY, Herlyn M. Regulation of MelCAM/MUC18 expression on melanocytes of different stages of
tumor progression by normal keratinocytes. Am J Pathol.
1994a Oct;145(4):837-45
Shih IM, Elder DE, Speicher D, Johnson JP, Herlyn M.
Isolation and functional characterization of the A32 melanomaassociated antigen. Cancer Res. 1994b May 1;54(9):2514-20
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.
Taira E, Nagino T, Taniura H, Takaha N, Kim CH, Kuo CH, Li
BS, Higuchi H, Miki N. Expression and functional analysis of a
novel isoform of gicerin, an immunoglobulin superfamily cell
adhesion molecule. J Biol Chem. 1995 Dec 1;270(48):28681-7
Bardin N, George F, Mutin M, Brisson C, Horschowski N,
Francés V, Lesaule G, Sampol J. S-Endo 1, a pan-endothelial
monoclonal antibody recognizing a novel human endothelial
antigen. Tissue Antigens. 1996 Nov;48(5):531-9
Xie S, Luca M, Huang S, Gutman M, Reich R, Johnson JP,
Bar-Eli M. Expression of MCAM/MUC18 by human melanoma
cells leads to increased tumor growth and metastasis. Cancer
Res. 1997 Jun 1;57(11):2295-303
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).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
Schlagbauer-Wadl H, Jansen B, Müller M, Polterauer P, Wolff
K, Eichler HG, Pehamberger H, Konak E, Johnson JP.
Influence of MUC18/MCAM/CD146 expression on human
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Shih IM. The role of CD146 (Mel-CAM) in biology and
pathology. J Pathol. 1999 Sep;189(1):4-11
Anfosso F, Bardin N, Vivier E, Sabatier F, Sampol J, DignatGeorge F. Outside-in signaling pathway linked to CD146
engagement in human endothelial cells. J Biol Chem. 2001 Jan
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and characterization of the major form of human MUC18 cDNA
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Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
This article should be referenced as such:
Wu GJ. MCAM (melanoma cell adhesion molecule). Atlas
Genet Cytogenet Oncol Haematol. 2012; 16(7):476-479.
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