CD99 - CD99 molecule |Elisa - Clia - Antibody - Protein

Background

CD99, also known as MIC2, is a cell surface glycoprotein expressed on various cell types, including leukocytes, endothelial cells, and certain tumor cells. The CD99 protein plays a role in multiple biological processes, such as cell adhesion, migration, apoptosis, and immune regulation. CD99 expression is crucial in thymocyte differentiation and T cell activation, as well as in leukocyte extravasation, where immune cells move from blood vessels to sites of inflammation. It is also involved in neural cell adhesion and spermatogenesis, highlighting its diverse functional roles across cell types and tissues.

CD99 has garnered attention for its clinical implications, especially in cancer, as it is overexpressed in Ewing sarcoma and other tumors, making it a biomarker of diagnostic and therapeutic interest. Additionally, CD99 is involved in the immune response, where it contributes to the regulation of leukocyte activity and inflammation. The molecule also plays a role in apoptosis, promoting cell death in specific contexts, and has a dual role in tumor biology, both enhancing and inhibiting tumor progression depending on the cancer type and tissue context.

Protein Structure

The CD99 molecule is an unusual cell surface protein because of its small size and single transmembrane domain structure, which diverges from the common structure of other cell adhesion molecules. CD99 consists of approximately 185 amino acids with a molecular weight of around 32 kDa, and it undergoes post-translational glycosylation, contributing to its stability and function on the cell surface.

Extracellular Domain:

• CD99 has a short extracellular domain, comprising around 122 amino acids. This domain contains two N-linked glycosylation sites, which are crucial for its stability and functional expression on the cell surface. Glycosylation is essential for mediating CD99’s interactions with other proteins and ligands.
• The extracellular domain mediates the adhesion functions of CD99 and plays a role in the homophilic interactions between CD99 molecules on opposing cell surfaces, enabling cell-cell adhesion.

Transmembrane Domain:

• CD99 has a single transmembrane helix, which anchors the protein to the plasma membrane. This transmembrane region consists of hydrophobic amino acids that enable CD99 to integrate stably within the lipid bilayer of the cell membrane.

Intracellular (Cytoplasmic) Domain:

• The cytoplasmic domain of CD99 is short, comprising roughly 20 amino acids. Despite its small size, this domain is critical for the intracellular signaling associated with CD99. It contains regions involved in phosphorylation, allowing the molecule to participate in signaling pathways that regulate cellular functions, such as apoptosis and T cell activation.
• This domain also interacts with cytoplasmic adaptor proteins and other signaling molecules, allowing CD99 to influence cellular processes.

Classification and Subtypes

CD99 is part of the CD (cluster of differentiation) family of proteins, which includes a wide variety of molecules involved in cell adhesion, signaling, and immune responses. Unlike other CD proteins, CD99 does not have closely related subtypes or isoforms with distinct functional roles. However, alternative splicing can give rise to minor isoforms of CD99 with slight differences in the extracellular region, though these variations do not significantly impact its primary functions or clinical relevance.

Function and Biological Significance

Cell Adhesion and Migration:

• CD99 is involved in homophilic cell-cell adhesion, where CD99 molecules on one cell interact with CD99 molecules on an adjacent cell. This function is important for cell aggregation and interaction within tissues, contributing to tissue integrity and immune responses.
• It is also crucial in leukocyte extravasation. CD99 helps guide immune cells from the bloodstream through the endothelium and into inflamed tissues, acting in coordination with other cell adhesion molecules like PECAM-1 (CD31).

Immune Regulation:

• CD99 plays a role in T cell activation and thymocyte differentiation in the thymus. It is expressed on thymocytes at various stages of development, where it facilitates the selection and maturation of T cells.
• CD99 is also expressed on neutrophils and monocytes, where it supports immune surveillance and contributes to inflammation by allowing immune cells to migrate to infection sites. By facilitating extravasation, CD99 indirectly enhances the immune response.

Apoptosis and Cell Death:

• CD99 can promote apoptosis, or programmed cell death, in specific cell types. It has been observed to mediate caspase-independent apoptosis in tumor cells, a property that may be harnessed in cancer treatment to induce cell death in tumors expressing high levels of CD99.
• In thymocytes, CD99 is involved in negative selection, where it helps eliminate immature T cells with self-reactive receptors, ensuring that the immune system does not target the body’s own tissues.

Tumor Biology:

• CD99 has a dual role in cancer biology. In certain tumors, such as Ewing sarcoma, CD99 is highly expressed and contributes to oncogenesis. It may promote tumor growth by enabling cell adhesion and migration, aiding the tumor's spread.
• In other cancer types, CD99 functions as a tumor suppressor, limiting cell proliferation and promoting apoptosis. This context-dependent role makes CD99 a complex target in cancer research, where it can either serve as a therapeutic target or a diagnostic marker.

Clinical Issues

Cancer:

• Ewing Sarcoma: CD99 is highly expressed in Ewing sarcoma, a rare bone and soft tissue cancer. The presence of CD99 on Ewing sarcoma cells is so consistent that it serves as a diagnostic marker for the disease. Anti-CD99 therapies are being explored as a potential treatment for Ewing sarcoma due to CD99's role in cell adhesion and growth in this cancer type.
• Other Tumors: CD99 expression is also observed in other malignancies, such as lymphomas, acute leukemias, and certain carcinomas. In these cancers, CD99 expression can influence cell adhesion, migration, and resistance to apoptosis, contributing to cancer progression.

Autoimmune and Inflammatory Diseases:

• Due to its role in immune cell migration and inflammation, CD99 is involved in inflammatory diseases where leukocyte extravasation is a key feature, such as rheumatoid arthritis and other autoimmune conditions. Research is exploring CD99 as a target for modulating immune responses and reducing inflammation in these diseases.

Potential in Immunotherapy:

• CD99’s role in immune cell activation and migration makes it a potential target in immunotherapy. By modulating CD99 activity, it may be possible to enhance or inhibit immune responses, providing therapeutic benefits in conditions ranging from cancer to autoimmune diseases.

Summary

CD99 is a small transmembrane glycoprotein with critical roles in cell adhesion, migration, immune regulation, and apoptosis. Structurally, CD99 contains a single transmembrane domain, a short extracellular domain with glycosylation sites, and a small cytoplasmic tail essential for signaling. Its primary functions include facilitating leukocyte extravasation, supporting T cell development in the thymus, and promoting apoptosis in specific cell contexts. CD99 is also notable in oncology, as it serves as a diagnostic marker in Ewing sarcoma and exhibits dual roles in tumor progression depending on the tissue context.

Clinically, CD99 is significant as a marker and therapeutic target in cancers like Ewing sarcoma, where it aids in tumor proliferation and migration. In immune and inflammatory diseases, CD99 influences leukocyte behavior, making it a potential target for treatments that seek to modulate immune responses.