Dipeptidyl Peptidase-4 Regulation of SDF-1/CXCR4 Axis: Implications for Cardiovascular Disease

Zhong, Jixin; Rajagopalan, Sanjay

identified as a new dipeptide naphthylamidase in 1966 (1) and subsequently found to be identical to T cell activation antigen CD26, ADA-binding protein, mouse thymocyte-activating molecule, and rat liver membrane glycoprotein gp110 (2) . DPP4 consists of a short N-terminal intracellular domain (6 residues), a 22-residue-long transmembrane α-helix domain (23 amino acids), and a large C-terminal extracellular domain. The C-terminal extracellular domain is responsible for its catalytic activity and binding to a number of ligands, such as ADA and matrix proteins (3) . The catalytic activity of DPP4 depends on its dimerization and glycosylation of specific residues (2) . DPP4 can also assemble into tetramers on the cell surface, which may involve the linkage of dimers located on the surface of two different cells, enabling it to function as a cell-cell communication molecule. In addition to its membrane-bound form, DPP4 also circulates as a soluble form in the plasma, which lacks the cytoplasmic and transmembrane domain with preserved catalytic activity. Soluble DPP4 (sDPP4) is a homodimer with a molecular weight range of 210-290 kDa (4), but can form higher molecular weight assemblies migrating as 900-kDa complexes (5) . Whether sDPP4 is cleaved from the membrane or is secreted is unclear. For instance, studies investigating viral liver infection suggested that sDPP4 is shed from membrane-bound DPP4 (6) . sDPP4 has, however, also been detected in the lumen of secretory granules in pancreatic α cells and in the exocytic secretory lysosomes of natural killer cells (7, 8) . sDPP4 is commonly elevated in many disorders, such as solid tumors, reactive airways disease, hepatitis C, type 2 diabetes, and obesity (6, 9, 10) .