CD26 is a protein found on the surface of cells throughout the body, playing a part in various biological processes. Its widespread presence highlights its importance in how cells and systems function.
What CD26 Is
CD26 is a glycoprotein, also known as dipeptidyl peptidase IV (DPP-IV). It is primarily located on the outer surface of cells as a transmembrane protein. This protein is found on a wide array of cell types, including immune cells, epithelial cells, and endothelial cells lining blood vessels.
The molecular structure of CD26 consists of two identical parts, forming a homodimer, each with a beta-propeller and an alpha/beta-hydrolase domain. It is anchored to the cell membrane by its N-terminal end, which includes a short cytoplasmic tail, a transmembrane region, and a larger extracellular portion. Beyond its enzymatic role, CD26 also functions as a receptor, interacting with other cell surface molecules.
How CD26 Functions
CD26 functions primarily through its enzymatic activity as DPP-IV. As a serine exopeptidase, it cleaves dipeptides from the N-terminus of various polypeptides. This cleavage preferentially occurs when the second amino acid is proline or alanine.
This enzymatic action impacts hormone regulation by influencing incretins like glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). CD26 also plays a role in cell adhesion, interacting with components of the extracellular matrix such as collagen and fibronectin. It also binds to other proteins, including adenosine deaminase (ADA).
CD26 is involved in immune regulation, particularly affecting T-cell activation and proliferation. Its expression on T cells, especially CD4+ helper/memory cells, increases upon activation, and it can deliver a co-stimulatory signal. This co-stimulation enhances T-cell proliferation, cytokine production, and cytotoxic properties. CD26 also interacts with other immune molecules like CD45, a protein tyrosine phosphatase, influencing signal transduction pathways within T cells.
CD26 and Its Role in Disease
CD26 plays a multifaceted role in various human diseases, often exhibiting a dual nature depending on the specific disease context. In cancer, its involvement is complex; it can act as a tumor suppressor in some cancers like melanoma, where its loss of expression is associated with malignant transformation. Conversely, CD26 can also promote tumor growth and metastasis in other cancers, with elevated levels found in thyroid, ovarian, and certain T-cell cancers. For example, in malignant pleural mesothelioma, CD26 is highly expressed and its presence correlates with tumor progression.
CD26 is also implicated in autoimmune disorders, where its altered expression and activity can contribute to inflammation and tissue damage. Elevated levels of CD26+ lymphocytes are observed in conditions like rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis, and these levels often correlate with disease severity. In autoimmune diabetes, increased CD26 activity is linked to the destruction of insulin-producing pancreatic cells. Inhibiting CD26 has shown potential in reducing inflammation and promoting anti-inflammatory responses in experimental models of colitis.
In metabolic disorders, particularly type 2 diabetes, CD26’s enzymatic activity directly affects glucose metabolism. It rapidly degrades incretin hormones, GLP-1 and GIP, which stimulate insulin secretion after meals. Increased CD26/DPPIV expression in tissues like adipose tissue and pancreatic islet cells is observed in obesity and diabetes. By cleaving these hormones, CD26 contributes to impaired glucose control.
CD26 as a Target for Therapies
Understanding CD26’s functions and its involvement in various diseases has led to its exploration as a therapeutic target. In type 2 diabetes, DPP-IV inhibitors, commonly known as gliptins, are established oral medications. These drugs block the enzymatic activity of CD26, preventing the rapid breakdown of incretin hormones like GLP-1 and GIP. This prolongs incretin presence, enhancing insulin secretion and lowering blood glucose levels.
Beyond diabetes, research is ongoing to target CD26 for other conditions, including cancer and autoimmune diseases. For instance, humanized anti-CD26 monoclonal antibodies are being investigated for their potential to inhibit tumor growth in cancers such as malignant mesothelioma and multiple myeloma. These antibodies can directly suppress tumor cell growth and induce cell death; some are in clinical trials. CD26 is also being explored as a potential diagnostic biomarker, with soluble CD26 levels in blood being investigated for early detection and monitoring of conditions like colorectal cancer and pancreatic tumors.