CD146

CD146 (cluster of differentiation 146) also known as the melanoma cell adhesion molecule (MCAM) or cell surface glycoprotein MUC18, is a 113kDa cell adhesion molecule currently used as a marker for endothelial cell lineage. In humans, the CD146 protein is encoded by the MCAM gene.[5]

MCAM
Identifiers
AliasesMCAM, CD146, MUC18, melanoma cell adhesion molecule, HEMETCAM, MelCAM
External IDsOMIM: 155735 MGI: 1933966 HomoloGene: 4742 GeneCards: MCAM
Orthologs
SpeciesHumanMouse
Entrez

4162

84004

Ensembl

ENSG00000076706

ENSMUSG00000032135

UniProt

P43121

Q8R2Y2

RefSeq (mRNA)

NM_006500

NM_023061
NM_001359530

RefSeq (protein)

NP_006491

NP_075548
NP_001346459

Location (UCSC)Chr 11: 119.31 – 119.32 MbChr 9: 44.05 – 44.05 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

MCAM functions as a receptor for laminin alpha 4,[6] a matrix molecule that is broadly expressed within the vascular wall. Accordingly, MCAM is highly expressed by cells that are components of the blood vessel wall, including vascular endothelial cells, smooth muscle cells and pericytes. Its function is still poorly understood, but evidence points to it being part of the endothelial junction associated with the actin cytoskeleton. A member of the Immunoglobulin superfamily, it consists of five Ig domains, a transmembrane domain, and a cytoplasmic region. It is expressed on chicken embryonic spleen and thymus, activated human T cells, endothelial progenitors such as angioblasts and mesenchymal stem cells, and strongly expressed on blood vessel endothelium and smooth muscle.

Two isoforms exist (MCAM long (MCAM-1), and MCAM short, or MCAM-s) which differ in the length of their cytoplasmic domain. Activation of these isoforms seems to produce functional differences as well. Natural killer cells transfected with MCAM-1 demonstrate decreased rolling velocity and increased cell adhesion to an endothelial cell monolayer and increased microvilli formation while cells transfected with MCAM-s showed no change in adhesion characteristics. Since these characteristics are important in leukocyte extravasation, MCAM-1 may be an important part of the inflammatory response.

CD146 has been demonstrated to appear on a small subset of T and B lymphocytes in the peripheral blood of healthy individuals. The CD146+ T cells display an immunophenotype consistent with effector memory cells and have a distinct gene profile from the CD146- T cells.[7][8] CD146 T cells have been shown by Dagur and colleagues to produce IL-17.[9]

CD146 has been seen as a marker for mesenchymal stem cells isolated from multiple adult and fetal organs,[10] and its expression may be linked to multipotency; mesenchymal stem cells with greater differentiation potential express higher levels of CD146 on the cell surface.[11]

Relevance in cancer

MCAM inhibits breast cancer progression.[12]

Normal melanocytes do not express MCAM and the expression of MCAM is first found in nevi and melanoma cells.[13] MCAM expression is positively correlated to melanoma progression at which the expression of MCAM is highest in metastatic melanoma cells. The significance of MCAM upregulation is evident in melanoma cells cultured in 3D skin reconstruct in which MCAM facilitates the migration of melanoma into the dermis. Without the expression of MCAM melanoma cells are controlled by keratinocytes in the epidermis that inhibit penetrance beyond the basement membrane. The control by keratinocytes are only achieved by E-cadherin expression on the surface of melanoma cells. Melanoma cells with functional E-cadherin on the surface can only exclusively grow in the epidermis as keratinocytes frequently downregulate the expression of MCAM on melanoma cells.[13]

References
  1. GRCh38: Ensembl release 89: ENSG00000076706 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000032135 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Kuske MD, Johnson JP (1999). "Assignment of the human melanoma cell adhesion molecule gene (MCAM) to chromosome 11 band q23.3 by radiation hybrid mapping". Cytogenetics and Cell Genetics. 87 (3–4): 258. doi:10.1159/000015439. PMID 10702685. S2CID 37508075.
  6. Flanagan K, Fitzgerald K, Baker J, Regnstrom K, Gardai S, Bard F, et al. (2012). "Laminin-411 is a vascular ligand for MCAM and facilitates TH17 cell entry into the CNS". PLOS ONE. 7 (7): e40443. Bibcode:2012PLoSO...740443F. doi:10.1371/journal.pone.0040443. PMC 3391262. PMID 22792325.
  7. Elshal MF, Khan SS, Takahashi Y, Solomon MA, McCoy JP (October 2005). "CD146 (Mel-CAM), an adhesion marker of endothelial cells, is a novel marker of lymphocyte subset activation in normal peripheral blood". Blood. 106 (8): 2923–4. doi:10.1182/blood-2005-06-2307. PMID 16204154.
  8. Elshal MF, Khan SS, Raghavachari N, Takahashi Y, Barb J, Bailey JJ, et al. (November 2007). "A unique population of effector memory lymphocytes identified by CD146 having a distinct immunophenotypic and genomic profile". BMC Immunology. 8: 29. doi:10.1186/1471-2172-8-29. PMC 2248207. PMID 17999761.
  9. Dagur PK, Biancotto A, Wei L, Sen HN, Yao M, Strober W, et al. (December 2011). "MCAM-expressing CD4(+) T cells in peripheral blood secrete IL-17A and are significantly elevated in inflammatory autoimmune diseases". Journal of Autoimmunity. 37 (4): 319–27. doi:10.1016/j.jaut.2011.09.003. PMC 3223259. PMID 21959269.
  10. Covas DT, Panepucci RA, Fontes AM, Silva WA, Orellana MD, Freitas MC, et al. (May 2008). "Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional properties and gene-expression profile with CD146+ perivascular cells and fibroblasts". Experimental Hematology. 36 (5): 642–54. doi:10.1016/j.exphem.2007.12.015. PMID 18295964.
  11. Russell KC, Phinney DG, Lacey MR, Barrilleaux BL, Meyertholen KE, O'Connor KC (April 2010). "In vitro high-capacity assay to quantify the clonal heterogeneity in trilineage potential of mesenchymal stem cells reveals a complex hierarchy of lineage commitment". Stem Cells. 28 (4): 788–98. doi:10.1002/stem.312. PMID 20127798. S2CID 45009922.
  12. Ouhtit A, Gaur RL, Abd Elmageed ZY, Fernando A, Thouta R, Trappey AK, et al. (April 2009). "Towards understanding the mode of action of the multifaceted cell adhesion receptor CD146". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1795 (2): 130–6. doi:10.1016/j.bbcan.2009.01.002. PMID 19356677.
  13. Haass NK, Smalley KS, Li L, Herlyn M (June 2005). "Adhesion, migration and communication in melanocytes and melanoma". Pigment Cell Research. 18 (3): 150–9. doi:10.1111/j.1600-0749.2005.00235.x. PMID 15892711.

Further reading
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