Cell-surface peptidases

Abstract

The cell surface has various functions: communicating with other cells, integrating into the tissue, and interacting with the extracellular matrix. Proteases play a key role in these processes. This review focuses on cell-surface peptidases (ectopeptidases, oligopeptidases) that are involved in the inactivation or activation of extracellular regulatory peptides, hormones, paracrine peptides, cytokines, and neuropeptides. The nomenclature of cell-surface peptidases is explained in relation to other proteases, and information is provided on membrane anchoring, catalytic sites, regulation, and, in particular, on their physiological and pharmacological importance. Furthermore, nonenzymatic (binding) functions and participation in intracellular signal transduction of cell surfaces peptidases are described. An overview on the different cell-surface peptidases is given, and their divergent functions are explained in detail. An example of actual pharmacological importance, dipeptidyl-peptidase IV (CD26), is discussed.

FIG. 1

Topology of cell-surface peptidases. Cell-surface peptidases are anchored in the plasma membrane either with a transmembrane region (schematic: lipid bilayer with helical lipophilic amino acid sequences; type I = N-terminus extracellular; type II = C-terminus extracellular), or they are linked to the membrane via a glycosyl-phosphatidylinositol (GPI) anchor. The extracellular region is highly glycosylated (schematic: hexoses). Secretases may liberate the extracellular parts of cell-surface peptidases to yield soluble variants.

FIG. 2

Localization of DPP IV. (A) Histochemical staining of DPP IV activity with Gly-Pro-4- methoxy-2-naphthylamide and a diazonium salt on a fresh section of porcine pancreas. Epithelial cells of the pancreatic duct and endothelial cells of blood vessels are stained red; blue: nuclear counterstaining with hemalum. (B) Immunostaining of human T lymphocytes with rabbit antihuman DPP IV followed by a fluoresceine-labeled secondary antibody. The green immunofluorescence covers the cell surface. (C) Preembedding immunostaining of cultivated endothelial cells (human umbilical vein endothelial cells) with rabbit antihuman DPP IV followed by a 20-nm gold-labeled secondary antibody. Staining is found on the cell surface, in endosomal pits, and in vesicles (probably caveolae). A coated pit (at the left) is immunonegative.

FIG. 3

Schematic representation of substrates cleaved by DPP IV. Dipeptides are liberated from the N-terminus of peptides with Pro or Ala in the P₁ position. Certain peptides with other small amino acids in the P₁ position are cleaved with low rates. In the P₂ position bulky, hydrophobic, or basic amino acids with an obligate free amino group are preferred. Peptides with Pro or Hyp in the P₁′ position are resistant to DPP IV.

FIG. 4

Schematic drawing of the role for DPP IV in the inactivation of incretins. GLP-1 and GIP are released postprandially from intestinal L or K cells, transported in the blood, and stimulate insulin secretion from pancreatic β-cells. DPP IV at the surface of endothelial cells or soluble in the blood degrades both peptides at the N-terminus resulting in a rapid loss of hormonal activity.