Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3).

Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13895-900.

Nykjaer A, Fyfe JC, Kozyraki R, Leheste JR, Jacobsen C, Nielsen MS, Verroust PJ, Aminoff M, de la Chapelle A, Moestrup SK, Ray R, Gliemann J, Willnow TE, Christensen EI.

Department of Medical Biochemistry, University of Aarhus, DK-8000 Aarhus C, Denmark. an@biokemi.au.dk

Steroid hormones are central regulators of a variety of biological processes. According to the free hormone hypothesis, steroids enter target cells by passive diffusion. However, recently we demonstrated that 25(OH) vitamin D(3) complexed to its plasma carrier, the vitamin D-binding protein, enters renal proximal tubules by receptor-mediated endocytosis. Knockout mice lacking the endocytic receptor megalin lose 25(OH) vitamin D(3) in the urine and develop bone disease. Here, we report that cubilin, a membrane-associated protein colocalizing with megalin, facilitates the endocytic process by sequestering steroid-carrier complexes on the cellular surface before megalin-mediated internalization of the cubilin-bound ligand. Dogs with an inherited disorder affecting cubilin biosynthesis exhibit abnormal vitamin D metabolism. Similarly, human patients with mutations causing cubilin dysfunction exhibit urinary excretion of 25(OH) vitamin D(3). This observation identifies spontaneous mutations in an endocytic receptor pathway affecting cellular uptake and metabolism of a steroid hormone.

PMID: 11717447

PDF is attached at the bottom of this page

---

From bowel to kidneys: the role of cubilin in physiology and disease

Erik I. Christensen⇓, Rikke Nielsen and Henrik Birn

Section of Cell Biology, Department of Biomedicine, Faculty of Health Sciences, Aarhus University, Aarhus, Denmark

Correspondence and offprint requests to: Erik Ilsø Christensen; E-mail: eic@ana.au.dk

Received September 11, 2012; Accepted October 29, 2012.

Cubilin is a large endocytic receptor serving such diverse functions as the intestinal absorption of the intrinsic factor–B12 complex and the renal proximal tubule reabsorption of filtered proteins including albumin, transferrin, vitamin D-binding protein and other important plasma carriers. Cubilin is a structurally unique, peripheral membrane protein, which depends on the membrane protein amnionless (AMN) for correct apical translocation. In addition, AMN appears important for efficient internalization of intrinsic factor–B12 in the intestine, whereas in the proximal tubule cubilin interacts with another endocytic receptor, megalin, for effective reabsorption. The importance of cubilin has been demonstrated in several animal models of cubilin deficiency as well as in a variety of human diseases. Recent demonstration of cubilin in podocytes from various species awaits further clarification with respect to the functional role as well as its role in pathology.

---

Comment by VitaminDWiki

Has not head of Cubilin before. Wonder if it is part of the reason for a 2X difference in vitamin D between individuals