Cell Surface ATP Synthase: A Potential Target for Anti-Angiogenic Therapy

Abstract

Since the presence of F1F0 adenosine triphosphate (ATP) synthase was discovered on the surface of human cells, numerous studies have elucidated new functions for this molecule that classically functions as part of the electron transport chain in mitochondria. Like mitochondrial ATP synthase, the cell surface form of this molecule functions as an energy-producing proton pump, coupling the production of extracellular ATP with the transport of protons outside the cell. ATP synthase also acts as an endothelial cell surface receptor for angiostatin, which has led several groups to examine this molecule as a target for inhibiting angiogenesis. Given its involvement in proton transport and the pH-dependent activity of angiostatin and antibodies directed against it, ATP synthase likely functions in part to regulate pH for endothelial cells existing in an acidic microenvironment. In addition, it catalyzes the synthesis and hydrolysis of ATP in the extracellular milieu, potentially affecting purinergic signaling. ATP synthase also plays a role in endothelial cell signaling in response to flow-induced shear stress. Recently, ATP synthase on the surface of endothelial cells has been identified as the receptor for two additional proteins: coupling factor 6 and endothelial monocyte-activating polypeptide II. This chapter will focus on the role of endothelial cell surface ATP synthase in angiogenesis, shear stress response, and as a receptor.