Megalin and cubilin: multifunctional endocytic receptors

Top Cited Papers
Publisher Website
Google Scholar
Abstract
Both megalin and cubilin are large, multiligand, endocytic-membrane glycoproteins. Megalin is a member of the low-density lipoprotein (LDL)-receptor family, which is composed of a large extracellular domain with several ligand-binding regions, a transmembrane domain and a short cytoplasmic tail with potential signal-activation sequences. Cubilin is a structurally very different peripheral membrane protein with no obvious transmembrane domain. The molecule is dominated by 27 CUB domains, which are involved in ligand binding. Megalin and cubilin are expressed in epithelial cells of several tissues, including intestine, kidney, lung, brain, tissues involved in maternal-to-fetal exchange, endocrine glands, sense organs and the genital system. Megalin and cubilin are involved in the endocytic uptake of many ligands, including lipoproteins, vitamin-binding proteins, other carrier proteins, hormones, enzymes and drugs in several epithelia. The receptors might work independently, but have also been shown to interact to facilitate the uptake of several ligands. Megalin deficiency in mice is associated with multiorgan dysfunction and the syndrome of holoprosencephaly. Cubilin dysfunction in dogs or humans is associated with the syndrome of hereditary megaloblastic anaemia 1 and proteinuria. Renal-tubular reabsorption and rescue of several filtered ligands, including hormones, vitamins and iron-carriers, is dependent on megalin and cubilin. In particular, the receptors are important for providing substrate for renal hydroxylation and activation of vitamin D. Megalin might also have a further role in calcium regulation by serving as a calcium-sensing protein in the parathyroid gland and by mediating uptake and degradation of parathyroid hormone. Megalin is involved in the regulation of thyroid-hormone production by the thyroid gland by mediating uptake and transcytosis of thyroglobulin. The endocytic uptake of nephro- and ototoxic drugs, such as aminoglycosides, can be mediated by megalin, which indicates a role in the development of tissue damage caused by these agents. Members of the LDL-receptor family can mediate intracellular signalling by binding of cytoplasmic adaptor proteins. Megalin has been shown to bind disabled protein 2, which indicates a role in signal transduction. Future research is expected to resolve the specific functions of megalin and cubilin in fetal development, in vitamin homeostasis, and for the targeted uptake of steroid-carrier protein complexes in specific tissues. New perspectives might originate from the evolving concept of signalling by endocytic receptors.

This publication has 122 references indexed in Scilit: