Role of Megalin in Endocytosis and Signaling

Megalin, a member of the LDL receptor gene family (Fig. 1), is a major endocytic receptor found in clathrin-coated pits. We originally identified megalin in our lab as the target antigen of an autoimmune glomerular disease, Heymann nephritis. In contrast to other members of the LDL receptor family, megalin is located on the apical (instead of the basolateral) domain of many epithelial cells, including those of the proximal tubule and lung, among others. Megalin specifically binds and internalizes a large variety of proteins and has crucial functions as megalin knock-out mice have severe brain, kidney and lung abnormalities. In the kidney megalin is the main endocytic receptor in the proximal tubule responsible for the absorption of many proteins from the glomerular filtrate. Our lab has characterized in the past the role of megalin in the pathogenesis of Heymann nephritis and the role of megalin in reabsorption of proteins by the proximal tubule epithelium. Currently we are attempting to define the functions of the cytoplasmic tail of megalin in megalin signaling and trafficking by defining proteins that interact with the cytoplasmic tail of megalin. Our recent work on megalin has focused on the interactions of the megalin tail with ARH, an adaptor protein that binds to megalin (Fig. 2) and facilitates megalin endocytosis apparently by escorting megalin through the endocytic system.