Megalin and cubilin: multifunctional endocytic receptors

Key Points

  • 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.

Abstract

The ability to take up substances from the surrounding environment not only provides cells with vital nutrients, but also enables the selective transport of substances from one compartment to another. Megalin and cubilin are two structurally different endocytic receptors that interact to serve such functions. Evidence has accumulated in recent years to indicate that these receptors have important functions in both normal physiology and pathology.

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Figure 1: The structure of cubilin and megalin.
Figure 2: Model of RAP function for the processing of megalin.
Figure 3: Organs that express megalin and cubilin.
Figure 4: The role of megalin and cubilin in endocytosis and transcellular transport.
Figure 5: Distribution of endogenous transferrin.

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DATABASES

Interpro

CUB

EGF-like repeats

YWTD motif

LocusLink

transferrin

Medscape DrugInfo

aprotinin

gentamicin

polymyxin B

OMIM

Alzheimer's disease

Dent's disease

Fanconi renotubular syndrome

Graves' disease

Imerslund–Gräsbecks disease

RAP

Swiss-Prot

albumin

apoE

ApoER2

aprotinin

clara cell secretory protein

ClC-5

cubilin

Dab1

DBP

endoglyosidase H

furin

lactoferrin

lipoprotein lipase

megalin

NHE3

prolactin

Reelin

thyroglobulin

VLDL receptor

Glossary

TYPE 1 CELL-SURFACE RECEPTOR

A transmembrane receptor protein with the carboxyl terminus residing in the cytoplasm.

SIGNAL PEPTIDE SEQUENCE

A stretch of 15–60 amino-acid residues, which direct the protein into, in this case, the endoplasmic reticulum.

LDLR FAMILY

The mammalian LDLR family consists of at least five membrane endocytic receptors, which share characteristic exodomain modules. The receptors mediate endocytic uptake of various ligands (for review, see Ref. 10).

COMPLEMENT-TYPE/LDLR CLASS A REPEATS

Repeats with homology to sequences in the complement component 9. In the low-density lipoprotein receptors, these are arranged in clusters of 2–11 and constitute the ligand-binding regions. Each consists of about 40 amino acids with six cysteine residues.

EPIDERMAL GROWTH FACTOR (EGF)-LIKE REPEATS

Cysteine-rich repeats of about 50 amino acids, with sequence homology to epidermal growth factor.

COATED PIT

An invagination of the plasma membrane, which is involved in receptor-mediated endocytosis. The cytoplasmic coat consists of adaptin and clathrin, which is involved in vesicle formation.

GLYCOSYLPHOSPHATIDYLINOSITOL (GPI)-ANCHOR

Proteins that are anchored to the non-cytoplasmic part of the membrane bilayer solely by a single molecule of glycosylphosphatidylinositol covalently linked lipid anchor added to the carboxyl terminus in the endoplasmic reticulum.

AMPHIPATHIC

In part hydrophilic and in part hydrophobic.

PALMITOYLATION

The coupling, in this case, of palmitic acid to a cysteine residue in cubilin.

β-TURNS

Stretches of amino acids that connect either β-sheets or α-helices in a protein.

PLACENTAL CYTOTROPHOBLAST

The inner trophoblastic layer (see trophoectodermic cells) of cells that give rise to the syncytiotrophoblast facing the maternal circulation and constitute a layer through which all substances must pass from the mother to the fetus.

GLOMERULAR PODOCYTES

Epithelial cells that line the outer surface of the glomerular capillaries and constitute part of the glomerular filtration barrier.

TYPE II PNEUMOCYTES

Cells that line the alveolar walls of the lungs. These cells are involved in the production of surfactant (reducing surface tension and protecting the alveoli from collapsing during exhalation), and are responsible for proliferating and repopulating the alveolar lining of the lung.

TROPHOECTODERMIC CELLS

The cells of the outer wall of the blastocyst that do not contribute to the formation of the embryo per se but finally develop into the fetal portion of the placenta.

BRUSH BORDER

The lumenal plasma membrane of specialized epithelial cells, which are characterized by closely aligned microvilli. These are characteristic of the proximal tubule of the kidney, the small intestine and other epithelia (see Fig. 4).

HNEL RETENTION SIGNAL

An endoplasmic reticulum (ER) retention signal that is similar to the sequence KDEL, which is required for the vesicular retrieval of ER-resident proteins from the Golgi network back to the ER. This is mediated by binding to specific receptors that are located in the Golgi network (also see Box 1).

FURIN-MEDIATED CLEAVAGE

Furin is a transmembrane serine protease, which is predominantly located in the trans-Golgi-network and immature secretory vesicles. It recognizes the RXXR sequence and cleaves a number of pro-proteins, including enzymes, hormones and receptors.

PROTEINURIA

The human urinary excretion of more than 150 mg of protein in a 24-hour period.

SCAVENGER RECEPTOR

From a general point of view, receptors that can bind and mediate the clearance of various ligands.

HOLOPROSENCEPHALY

An inborn cranial defect, which is characterized by fusion of midline structures in the brain and face.

ENTEROCYTE

The absorptive epithelial cell of the intestine.

TRANSFERRIN

A metal-binding protein with a preference for ferric iron. Serum transferrin with a molecular weight of about 80 kDa transports iron from sites of absorption and storage to sites where it is used.

THYROCYTE

The hormone-producing cell of the thyroid gland. The cells synthesize thyroglobulin, which is secreted into a follicular lumen, iodinated, subsequently reabsorbed and then partly degraded in lysosomes to release the active thyroid hormones.

TRANSCYTOSIS

Transport of substances across epithelial cells, which involves endocytic internalization at one pole of the cell and exocytic release at another.

POLYBASIC DRUGS

Drugs that have a net positive charge at neutral pH. Here, these include aminoglycoside antibiotics, polymyxin B and aprotinin.

OTOTOXIC

Drugs that may damage the hearing and balance organs that are located in the inner ear, notably aminoglycoside antibiotics.

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Christensen, E., Birn, H. Megalin and cubilin: multifunctional endocytic receptors. Nat Rev Mol Cell Biol 3, 258–267 (2002). https://doi.org/10.1038/nrm778

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