Dipeptidyl peptidase-4 (DPP-4), also known as CD26, is the protease responsible for processing and inactivating both Glucagon-like peptide-1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP) by cleaving the peptide bond at the position 2 alanine residue of the N-terminus. DPP-4 preferentially cleaves polypeptides with a proline or alanine at the position 2. DPP-4 activity was initially detected in serum approximately 30 years ago.
DPP-4 is a ubiquitous, multifunctional, homodimeric type II cell surface glycoprotein existing in two principal forms; a membrane anchored, largely extracellular protein capable of stimulation of intracellular signal transduction pathways independent of its enzymatic activity, and a circulating soluble protein which retains enzymatic activity, but can no longer transmit signal directly into the cell. DPP-4 has been shown to be expressed on T cells, B cells and natural killer cells, as well as on endothelial, epithelial and acinar cells in a range of tissues. In humans, immunohistochemistry has detected DPP-4 in the endothelial layer of blood vessels, exocrine pancreas, kidney, uterus, sections of the gastrointestinal tract, and in the adrenal, parotid, sweat, salivary and mammary glands. DPP-4 is also present in the epithelial layer of the liver, lungs, brain and spleen.
Incretin hormones are release from the intestine following ingestion of a meal, and act on pancreatic P-cells to stimulate insulin secretion. The incretin effect, potentiated by GLP-1 and GIP, has been estimated to account for approximately 70% of total insulin secretion in healthy individuals in response to oral glucose. Insulinotropic actions of GIP and GLP-1 are mediated by DPP-4, and it is estimated that more than 50% of GLP-1 that leaves the intestine has already been degraded by DPP-4. Glucagon increases blood glucose levels, and DPP-4 inhibitors reduce glucagon and blood glucose levels. The mechanism of DPP-4 inhibitors is to increase incretin levels (GLP-1 and GIP), which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.
DPP-4 in immune responses and cancer
DPP-4 is expressed on T lymphocytes, B lymphocytes and NK cells. Detailed studies of subsets of human CD4+ T helper cells show that DPP-4 expression is more restricted than most other immune accessory proteins, as DPP-4 is expressed only on CD4+ memory T helper cells, which induce immunoglobulin formation in B cells and activate cytotoxic T-cells. Furthermore, CD4+ T-cells lacking DPP-4 can respond to mitogens and alloantigens, but do not perform helper functions. DPP-4 co-stimulates both CD2 and CD3 dependent T-cell activation, and initiates a signaling pathway involving intracellular calcium mobilization. The co-stimulatory actions of DPP-4 include increased T-cell responses to foreign antigens, and initiation of signal transduction. This results in increased cytokine secretion and upregulation of T-cell activation markers (i.e. CD69, CD71 and CD25), resulting in the above mentioned helper functions for B cells and cytotoxic T-lymphocytes. The signal transduction pathway of DPP-4 outlined in T-cells overlaps with the T-cell receptor/CD3 pathway, increasing tyrosine phosphorylation of P56lck, p59fyn, ZAP-70, phospholipase C-y, MAPK and c-Cbl. Malignant cancer cells often show altered DPP-4 expression, where the DPP-4 present in these cells can act as both a tumor suppressor or activator. DPP-4 is also capable of binding to extracellular matrices, leading to increased invasive activity of the cells on which it is expressed.
Reference:Meghan Sauve. Genetic Elimination or Partial Selective Inhibition of DPP-4 Activity and Outcomes Following Experimental Ischemic Cardiac Injury in the Mouse