New Insights into the Roles of Megalin/LRP2 and the Regulation of its Functional Expression

Abstract

Since the discovery of the low-density lipoprotein receptor (LDLR) and its association with familial hypercholesterolemia in the early 1980s, a family of structurally related proteins has been discovered that has apolipoprotein E as a common ligand, and the broad functions of its members have been described. LRP2, or megalin, is a member of the LDLR family and was initially called gp330. Megalin is an endocytic receptor expressed on the apical surface of several epithelial cells that internalizes a variety of ligands including nutrients, hormones and their carrier proteins, signaling molecules, morphogens, and extracellular matrix proteins. Once internalized, these ligands are directed to the lysosomal degradation pathway or transported by transcytosis from one side of the cell to the opposite membrane. The availability of megalin at the cell surface is controlled by several regulatory mechanisms, including the phosphorylation of its cytoplasmic domain by GSK3, the proteolysis of the extracellular domain at the cell surface (shedding), the subsequent intramembrane proteolysis of the transmembrane domain by the gamma-secretase complex, and exosome secretion. Based on the important roles of its ligands and its tissue expression pattern, megalin has been recognized as an important component of many pathological conditions, including diabetic nephropathy, Lowe syndrome, Dent disease, Alzheimer's disease (AD) and gallstone disease. In addition, the expression of megalin and some of its ligands in the central and peripheral nervous system suggests a role for this receptor in neural regeneration processes. Despite its obvious importance, the regulation of megalin expression is poorly understood. In this review, we describe the functions of megalin and its association with certain pathological conditions as well as the current understanding of the mechanisms that underlie the control of megalin expression.

Conserved Ankyrin Repeat Proteins and Their NIMA Kinase Partners Regulate Extracellular Matrix Remodeling and Intracellular Trafficking inCaenorhabditis elegans

“…Consistent with this, cholesterol is essential for molting in C. elegans (Yochem et al 1999;Merris et al 2003;Entchev and Kurzchalia 2005;Roudier et al 2005). In addition, studies on mammalian megalin suggest that C. elegans LRP-1 could promote molting in part by regulating the uptake of proteases and protease inhibitors (May et al 2007;Marzolo and Farfan 2011;Etique et al 2013). In addition to LRP-1, several other genes required for molting also affect intracellular trafficking and sterol-LRP-1 uptake including dab-1/Disabled, hgrs-1/VPS27, and sec-23/ SEC23 (Kamikura and Cooper 2003;Roberts et al 2003;Roudier et al 2005;Holmes et al 2007;Yochem et al 2015).…”

Mouse early extra-embryonic lineages activate compensatory endocytosis in response to poor maternal nutrition

“…We found both blastocyst TE and EB PE-like lineages activate enhanced endocytosis in response to maternal Emb-LPD with increased uptake of endocytosed fluid and ligand and increased numbers of lysosomes. These responses are accompanied by an increase in expression of the major LDLreceptor family member, megalin (Moestrup and Verroust, 2001;Marzolo and Farfán, 2011) in both extra-embryonic lineages. Moreover, diet-induced enhanced endocytosis is maintained upon in vitro culture in medium with standard composition; this stability is most striking in our EB model of PE-like cells, maintained over many passages from original derivation of ESCs from Emb-LPD blastocysts.…”

Multifarious effects of 17-β-estradiol on apolipoprotein E receptors gene expression during osteoblast differentiation <i>in vitro </i>

“…Named megalin because of its huge molecular structure, and is a member of the LDLR family also called LRP2 that is abundantly expressed in different epithelial cell types (66). Megalin is involved in embryonic renal development, including vitamin D homeostasis, sex hormone signaling, and holoprosencephaly (51,(67)(68)(69).…”