The elegant complexity of mammalian ecto-5′-nucleotidase (CD73)

Abstract

Purinergic signaling is a fundamental mechanism used by all cells to control their internal activities and interact with the environment. A key component of the purinergic system, the enzyme ecto-5′-nucleotidase (CD73) catalyzes the last step in the extracellular metabolism of ATP to form adenosine. Efforts to harness the therapeutic potential of endogenous adenosine in cancer have culminated in the ongoing clinical development of multiple CD73-targeting antibodies and small-molecule inhibitors. However, recent studies are painting an increasingly complex picture of CD73 mRNA and protein regulation and function in cellular homeostasis, physiological adaptation, and disease development. This review discusses the latest conceptual and methodological advances that are helping to unravel the complexity of this important enzyme that was identified nearly 90 years ago. CD73 is an integral component of the purinergic systemCells produce and consume ATP in a tightly regulated manner to ensure optimal organismal function. In addition to being used as fuel for essential activities within the cell, ATP is also released outside of the cell, where the sequential removal of its phosphate groups results in the formation of the nucleoside adenosine. Extracellular ATP and adenosine, together with associated synthetic and catabolic enzymes, receptors, and transporters, are part of the evolutionarily conserved purinergic system which links cellular metabolism to a myriad of other processes, including proliferation, differentiation, and cell death [1].

Decreased CD73+ Double-Negative T Cells and Elevated Level of Soluble CD73 Correlated With and Predicted Poor Immune Reconstitution in HIV-Infected Patients After Antiretroviral Therapy

“…Finally, the purinergic signaling is a complex network including a number of purinergic ligands, receptors, enzymes, channels, and transporters. In addition to CD73, many other purine-metabolizing enzymes, including adenosine deaminase (ADA), CD38, ATP-degrading enzymes like ENPPs and CD39, as well as ATP-regenerating kinases were also present in human plasma ( 78 , 84 – 86 ). Thus, the plasma concentration of ADO could be mediated by multiple pathways, implying a complicated relationship of ADO with CD73-expressing cells or sCD73.…”

Extracellular Nucleotides Affect the Proangiogenic Behavior of Fibroblasts, Keratinocytes, and Endothelial Cells

“…Some compounds, particularly ADP and ATP and their phosphorothioate analogs, showed a significant effect in HUVECs, with ATPγS being the most effective, probably activating P2Y2 and/or P2Y11 receptors. Literature data indicate that P2Y11 is a more likely candidate because the phosphorothioate analog of ATP is a more potent receptor agonist than unmodified ATP [ 33 ]. A slight stimulation was also observed in HUVECs cultured in the presence of nucleoside 5′-O-monophosphorothioates.…”

MicroRNA: Crucial modulator in purinergic signalling involved diseases

“…And it was reported to be modulated by miR-186, miR-150, miR-216b, and miR-21 in diverse cancers. As a major enzymatic source of extracellular adenosine in the purinergic signalling system, CD73 hydrolyzes AMP to adenosine which is able to activate the four adenosine receptors: A 1 , A 2A , A 2B , A 3 [9]. Beyond that, CD73 is a signal and adhesive molecule that modulates cell interaction with extracellular matrix components, so that plays a pivotal role in mediating the invasive and metastatic properties of cancers [31][32][33].…”

“…acting as endogenous ligands that bind to and activate plasmalemmal purinergic receptors (P1 receptors and P2 receptors), which mediate extracellular communication [7]. In addition, some associated ecto-enzymes, such as CD39, CD73, and adenosine deaminase (ADA), also get involved in Purinergic signalling [8,9]. P1 receptors are G protein-coupled receptors (GPCRs) that recognize adenosine as endogenous ligand and are divided into four subtypes known as A 1 , A 2A , A 2B , and A 3 receptors.…”