Proteins are fundamental to virtually all biological processes. A protein known as Transmembrane and Immunoglobulin Domain Containing 2, or TMIGD2, has recently captured the attention of the scientific community. This article will discuss the nature of TMIGD2, its biological activities, and its emerging relevance in health and disease.
What is TMIGD2?
TMIGD2 is a protein encoded by the TMIGD2 gene, located on chromosome 19 in humans, and is also referred to as IGPR-1 or CD28H. As a type I transmembrane protein, TMIGD2 is embedded in the cell’s outer membrane, acting as a bridge between the cell’s interior and its external environment. This position allows it to participate in communication and interactions with other cells.
TMIGD2 belongs to the immunoglobulin (Ig) superfamily, a large group of proteins involved in recognition, binding, and adhesion. Its architecture includes an extracellular portion with a single Ig-like domain, a segment that passes through the cell membrane, and a tail that extends into the cell’s cytoplasm. This cytoplasmic tail contains sites that can be chemically modified, allowing it to transmit signals within the cell.
Its expression is specific to certain cell types. It is present on the surface of epithelial cells, which line organs and blood vessels, and endothelial cells, which form the inner lining of blood vessels. The protein is also found on specific immune cells, most notably on naive T-cells (T-cells that have not yet encountered an antigen) and on natural killer (NK) cells. However, its expression on T-cells can be lost after repeated stimulation.
The Biological Roles of TMIGD2
One of TMIGD2’s well-documented roles is in cell adhesion. By binding to identical TMIGD2 proteins on adjacent cells, a process known as homophilic interaction, it helps cells stick together. This function is important for maintaining the integrity of tissues, particularly the endothelial barrier that lines blood vessels.
Beyond adhesion, TMIGD2 is involved in regulating cell migration and the formation of new blood vessels, a process called angiogenesis. Studies show that the level of TMIGD2 expression on endothelial cells can influence their ability to form capillary-like structures. The protein interacts with the cell’s internal scaffolding, or cytoskeleton, to modulate cellular shape and movement, which are necessary for these processes.
On T-cells, it acts as a costimulatory receptor, providing a secondary signal that enhances the primary activation signal when the T-cell encounters a foreign substance. When TMIGD2 binds to its partner molecule, HHLA2, on another cell, it triggers an internal signaling cascade involving the AKT pathway. This promotes T-cell proliferation and the production of signaling molecules called cytokines, which helps mount an effective immune response.
TMIGD2 in Health and Disease
The dysregulation of TMIGD2 is associated with several human diseases, particularly cancer. In some malignancies, such as certain gliomas (brain tumors), higher expression of TMIGD2 has been linked to a better prognosis. In these cases, it is associated with an increased infiltration of anti-tumor immune cells like NK cells and naive T-cells into the tumor microenvironment.
Conversely, in other cancers, elevated TMIGD2 expression is associated with a poor outcome. For instance, in gastric cancer, high levels of TMIGD2, especially when its binding partner HHLA2 is also present, predict a worse prognosis. Similarly, in oral squamous cell carcinoma, increased TMIGD2 expression correlates with unfavorable clinical parameters, suggesting its functions may be co-opted to support tumor growth.
The protein’s involvement is also being investigated in acute myeloid leukemia (AML), a cancer of the blood and bone marrow. Research has shown that TMIGD2 is aberrantly expressed on leukemia stem cells, which are responsible for initiating and sustaining the disease. In this context, TMIGD2 appears to promote the proliferation of AML cells while hindering their differentiation into mature myeloid cells, thereby contributing to the maintenance of the leukemia.
TMIGD2 Research and Therapeutic Prospects
The connection between TMIGD2 and various diseases has made it a potential target for new medical treatments. Scientists are working to fully understand why its expression leads to different outcomes in different cancers. This research involves mapping its precise signaling pathways and identifying other molecules it interacts with to carry out its functions.
One promising avenue is the development of TMIGD2 as a biomarker. Because its expression levels are altered in certain diseases, it could be used for diagnostic or prognostic purposes. For example, measuring TMIGD2 levels in tumor samples might help predict a patient’s clinical outcome or their likely response to specific immunotherapies. In glioma, it has been suggested as a relevant biomarker for patient selection for such treatments.
For cancers where TMIGD2 promotes growth, such as AML, researchers are exploring the use of monoclonal antibodies designed to block its activity. Preclinical studies have shown that such antibodies can slow the self-renewal of leukemia stem cells and reduce the overall leukemia burden in animal models, without significantly harming normal blood stem cells. Conversely, for cancers where TMIGD2 stimulates a helpful immune response, therapies could be designed to enhance its function, turning it into a tool against the tumor.