Paladin is a PI(4,5)P2 phosphoinositide phosphatase that regulates endosomal signaling and angiogenesis

Abstract

Cell signaling governs cellular behavior and is therefore subject to tight spatiotemporal regulation. Signaling output is regulated by specialized cell membranes and vesicles which contain unique combinations of lipids and proteins. The phospholipid phosphatidylinositol 4,5-bisphosphate, (PI(4,5)P2), an important component of the plasma membrane as well as other subcellular membranes, is involved in multiple processes, including signaling. However, which enzymes drive the formation and degradation of non-plasma membrane PI(4,5)P2, and their impact on cell signaling and function at the organismal level are unknown. Here we show in a mouse model that Paladin is a vascular PI(4,5)P2 phosphatase that regulates endosomal signaling and angiogenesis. Paladin was localized to the endosomal and Golgi compartments, and interacted with vascular endothelial growth factor receptor 2 (VEGFR2) in vitro and in vivo. Loss of Paladin resulted in increased internalization of the receptor, over-activation of extracellular regulated kinase, and hypersprouting of endothelial cells in the developing retina of mice. These findings suggest that inhibition of Paladin, or other endosomal PI(4,5)P2 phosphatases, could be exploited to modulate VEGFR2 signaling and angiogenesis, when direct and full inhibition of the receptor is not desirable.