Ecto‐phosphodiesterase/pyrophosphatase of lymphocytes and non‐lymphoid cells: structure and function of the PC‐1 family

Abstract

Many developmentally regulated membrane proteins of lymphocytes are ecto-enzymes, with their active sites on the external surface of the cell. These enzymes commonly have peptidase, phosphodiesterase or nucleotidase activity. Their biological roles are just beginning to be discovered. Although their expression is usually associated with particular stages of lymphoid differentiation, the same gene products are often expressed on the surface of certain non-lymphoid cell types outside the immune system, indicating that their functions cannot be unique to lymphocytes, nor can they be ubiquitous. The plasma cell membrane protein PC-1 (phosphodiesterase I; EC 3.1.4.1/nucleotide pyrophosphatase; EC 3.6.1.9), which was one of the first serological markers for lymphocyte subsets to be discovered, is a typical example. Within the immune system, PC-1 is confined to plasma cells, which represent about 0.1% of lymphocytes. However, PC-1 is also expressed on cells of the distal convoluted tubule of the kidney, chondrocytes, osteoblasts, epididymis and hepatocytes. Recent work has shown that PC-1 is a member of a multigene family of ecto-phosphodiesterases that currently has two other members, PD-1 alpha (autotaxin) and PD-1 beta (B10). Within this family, the extracellular domains are highly conserved, especially around the active site. In contrast, the transmembrane and cytoplasmic domains are highly divergent. Individual members of the eco-phosphodiesterase family have distinct patterns of distribution in different cell types, and even within the same cell. For example, PC-1 is present only on the basolateral surface of hepatocytes, while B10 (PD-1 beta) is confined to the apical surface. Analysis of conservation and differences in the sequence of their cytoplasmic tails may illuminate intracellular targetting signals. Ecto-phosphodiesterases may play a part in diverse activities in different tissues, including recycling of nucleotides. They may also regulate the concentration of pharmacologically active extracellular compounds such as adenosine or its derivatives and cell motility. Some members may modulate local concentrations of pyrophosphate, and hence influence calcification in bone and cartilage.

NAD+ and ATP Released from Injured Cells Induce P2X7-Dependent Shedding of CD62L and Externalization of Phosphatidylserine by Murine T Cells

“…8 and 9), in accord with previous studies (56,71). Enzymes capable of reversing ADP-ribosylation include ADP-ribosylhydrolases which can remove the entire ADP-ribose moiety (72,73) and phosphodiesterases which remove only AMP, leaving ribose phosphate attached to the target protein (74). To date ADP-ribosylhydrolases have been described only as intracellular proteins (75), whereas phosphodiesterase isoforms have been cloned and characterized that function as membrane bound and secretory ecto-enzymes (76,77).…”

F1-Adenosine Triphosphatase Displays Properties Characteristic of an Antigen Presentation Molecule for Vγ9Vδ2 T Cells

“…It seems likely that tumor cells or APCs can provide an NPP activity that is missing or poorly expressed on T cells. Although candidate ecto-enzymes have been reported on tumoral and nontumoral tissues (31,32), the persistence of phosphoantigenic activity on the cell surface implies that the postulated NPP activity is active only after encounter with T cells. This could be achieved through Ag release from the presenting molecule or through a local activation of the NPP activity concomitantly with TCR binding.…”

Extracellular nucleotide metabolism and signaling in the pathophysiology of articular cartilage

“…The widespread NPP1 (PC-1) was first identified as a serologic marker of human lymphocytes (41). NPP2␣ (PD-1␣, autotaxin) is secreted by human melanoma cells and stimulates motility at subnanomolar concentrations (42).…”

“…NPP4 and NPP5 are currently described as putative E-NPPs (46). Although defined as intrinsic membrane proteins, soluble forms of NPP1, NPP2␣, and NPP3 are detected in plasma (41,47).…”

“…Several tissues that synthesize collagenous extracellular matrices express NPP1, NPP2␣, and NPP3 (36,41,48,51). All 3 ectoenzymes have been immunolocalized in human knee menisci (36), whereas human articular chondrocytes transcribe mRNA for NPP1 and NPP3 (48).…”