MCAM - melanoma cell adhesion molecule | Elisa - Clia - Antibody - Protein

Background

The melanoma cell adhesion molecule (MCAM), also known as CD146 or MUC18, is a transmembrane glycoprotein belonging to the immunoglobulin superfamily (IgSF). MCAM was initially identified as an adhesion molecule highly expressed in melanoma cells, and since then, it has been shown to play a role in various cellular processes beyond melanoma, including angiogenesis, inflammation, and immune cell trafficking. MCAM is expressed in a variety of cell types, such as endothelial cells, smooth muscle cells, and immune cells, contributing to its diverse biological functions. Its key role in cellular adhesion makes it critical in both normal physiological processes like vascular integrity and in pathological conditions such as cancer metastasis, cardiovascular disease, and inflammation.

Protein Structure

MCAM is a type I transmembrane glycoprotein that has a structure of approximately 650 amino acids, with a molecular weight of around 113 kDa when glycosylated. Its protein structure is subdivided into three major domains:

Extracellular Domain (ECD):

• The extracellular region of MCAM contains five Ig-like domains that are characteristic of the immunoglobulin superfamily (IgSF). These domains contribute to its adhesive properties, allowing homophilic (self-binding) and heterophilic (binding to different molecules) interactions with other cells and the extracellular matrix.
• The first two Ig domains (IgV domains) are located at the distal end and are essential for ligand recognition and binding. This part of the protein facilitates binding interactions with several ligands, including laminins, galectins, and integrins, which are essential for cell adhesion and migration.
• The remaining three Ig domains (IgC2-type domains) serve as structural support, maintaining the overall integrity of the extracellular portion. Additionally, the extracellular domain is glycosylated at specific asparagine (N-linked) sites, which influences MCAM’s stability, interactions, and function.

Transmembrane Domain (TMD):

• The transmembrane domain of MCAM is a single-pass α-helical segment that anchors the protein in the cell membrane. This domain plays a structural role, providing stability to the protein as well as allowing lateral interactions with other membrane proteins, which can impact cellular signaling pathways.

Cytoplasmic Domain:

• The cytoplasmic tail of MCAM is relatively short but plays a key role in signal transduction. It is capable of interacting with cytoskeletal proteins, including actin-associated proteins. Through this domain, MCAM transmits extracellular signals to the cell interior, influencing cellular responses such as migration, proliferation, and survival.
• Tyrosine and serine residues in the cytoplasmic domain can be phosphorylated, which regulates its interactions with intracellular signaling molecules, such as focal adhesion kinase (FAK) and PI3K, influencing pathways involved in cellular adhesion and migration.

Classification and Subtypes

MCAM is classified as a member of the immunoglobulin superfamily (IgSF) and specifically as a cell adhesion molecule (CAM). Although it shares similarities with other adhesion molecules like ICAMs and VCAMs, MCAM's unique structure and ligand interactions distinguish it within the IgSF. MCAM does not have known subtypes or isoforms, although variations in glycosylation can affect its function and interactions across different cell types.

Function and Biological Significance

Cell Adhesion and Migration:

• MCAM facilitates both homophilic and heterophilic cell adhesion. In endothelial cells, it promotes cell-cell adhesion, contributing to vascular integrity. It can also interact with integrins on adjacent cells, mediating cell-matrix adhesion critical for tissue structure.
• MCAM plays a role in cell migration, especially in tumor cells, by interacting with extracellular matrix components and facilitating cell movement. This is particularly relevant in cancer metastasis, where MCAM expression aids in the detachment of cancer cells from the primary tumor and their movement to distant tissues.

Angiogenesis:

• MCAM is highly expressed in vascular endothelial cells, where it contributes to angiogenesis by promoting endothelial cell migration, proliferation, and tube formation. Its role in vascular development is essential for wound healing and tissue repair.
• Through interactions with signaling molecules like vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), MCAM supports the formation of new blood vessels, a process that can be co-opted by tumors to sustain their growth.

Immune Cell Trafficking and Inflammation:

• MCAM is expressed on certain immune cells, including subsets of T cells and natural killer (NK) cells. On T cells, MCAM aids in their adhesion and migration, allowing these cells to access inflamed tissues, which is essential for immune surveillance and response.
• In inflammatory conditions, MCAM expression on endothelial cells and leukocytes supports the extravasation of immune cells from the bloodstream into tissues, facilitating immune cell infiltration into areas of inflammation.

Cancer Progression and Metastasis:

• In melanoma and other aggressive cancers, MCAM expression is often upregulated. High levels of MCAM expression are associated with increased tumor invasiveness, metastatic potential, and poor patient prognosis.
• MCAM promotes tumor cell adhesion to endothelial cells and extracellular matrix proteins, facilitating intravasation (entry into blood vessels) and extravasation (exit from blood vessels), key steps in metastasis.

Clinical Issues

Cancer:

• Due to its role in cancer progression, MCAM has been studied as a potential target in various cancers, including melanoma, breast cancer, prostate cancer, and ovarian cancer. High MCAM expression is linked to poor prognosis and increased metastasis, especially in melanoma.
• Therapeutic strategies targeting MCAM are being developed to inhibit tumor growth and metastasis. These include monoclonal antibodies designed to block MCAM's interactions, thereby preventing cancer cells from adhering to the vascular endothelium and reducing metastasis.

Cardiovascular Diseases:

• MCAM’s role in endothelial cell adhesion and vascular integrity suggests it may contribute to cardiovascular conditions when dysregulated. For example, MCAM expression on endothelial cells can be elevated in atherosclerosis, where it may contribute to the adhesion of inflammatory cells to blood vessels, exacerbating plaque formation and vascular inflammation.

Inflammatory Diseases:

• Inflammatory diseases, including rheumatoid arthritis, exhibit increased MCAM expression, which supports the recruitment of immune cells to sites of inflammation. This increased expression facilitates leukocyte extravasation, intensifying the inflammatory response and tissue damage.
• Targeting MCAM could represent a therapeutic strategy to reduce excessive immune cell infiltration and inflammation in autoimmune and chronic inflammatory diseases.

Summary

MCAM, or melanoma cell adhesion molecule (CD146/MUC18), is a transmembrane glycoprotein and member of the immunoglobulin superfamily, crucial in mediating cell-cell and cell-matrix adhesion. Structurally, MCAM is composed of five extracellular Ig-like domains that enable adhesive interactions, a transmembrane domain for membrane anchoring, and a cytoplasmic tail that interacts with signaling molecules involved in cytoskeletal dynamics. Functionally, MCAM is essential for maintaining vascular integrity, promoting angiogenesis, supporting immune cell trafficking, and facilitating cell migration. These roles make MCAM relevant in physiological processes such as immune surveillance and tissue repair, but also in pathological conditions like cancer metastasis, cardiovascular disease, and inflammation. In cancer, MCAM is highly expressed in aggressive tumors, aiding tumor cell adhesion and migration, which drives metastasis. Additionally, MCAM’s involvement in inflammation and immune cell migration links it to inflammatory diseases and autoimmune conditions. Due to its pivotal roles in disease progression, MCAM has become a promising therapeutic target, with ongoing research exploring its inhibition to limit tumor growth and reduce inflammation.