Cubilin Explained

Cubilin is a protein that in humans is encoded by the CUBN gene.^{[1] [2] [3]}

Function

Cubilin (CUBN) acts as a receptor for intrinsic factor-vitamin B₁₂ complexes. The role of receptor is supported by the presence of 27 CUB domains. Cubilin shows a restricted mode of expression according to protein profiling and transcriptomics analyses,^[4] and is essentially only present in the kidneys and small intestine.^[5] Mutations in CUBN may play a role in autosomal recessive megaloblastic anemia.^[3] A complex of amnionless and cubilin forms the cubam receptor.

Clinical significance

Cubilin is a potential diagnostic and prognostic cancer biomarker for kidney cancer.^[6] Based on patient survival data, high levels of cubilin in tumor cells is a favourable prognostic biomarker in renal cell carcinoma.^{[7] [8]}

Further reading

• Christensen EI, Birn H . Megalin and cubilin: multifunctional endocytic receptors. . Nat. Rev. Mol. Cell Biol. . 3 . 4 . 256–66 . 2002 . 11994745 . 10.1038/nrm778 . 21893726 .
• Bork P, Beckmann G . The CUB domain. A widespread module in developmentally regulated proteins. . J. Mol. Biol. . 231 . 2 . 539–45 . 1993 . 8510165 . 10.1006/jmbi.1993.1305 .
• Birn H, Verroust PJ, Nexo E . Characterization of an epithelial approximately 460-kDa protein that facilitates endocytosis of intrinsic factor-vitamin B₁₂ and binds receptor-associated protein. . J. Biol. Chem. . 272 . 42 . 26497–504 . 1997 . 9334227 . 10.1074/jbc.272.42.26497 . etal. free .
• Batuman V, Verroust PJ, Navar GL . Myeloma light chains are ligands for cubilin (gp280). . Am. J. Physiol. . 275 . 2 Pt 2 . F246–54 . 1998 . 9691015 . 10.1152/ajprenal.1998.275.2.F246. etal.
• Lindblom A, Quadt N, Marsh T . The intrinsic factor-vitamin B₁₂ receptor, cubilin, is assembled into trimers via a coiled-coil alpha-helix. . J. Biol. Chem. . 274 . 10 . 6374–80 . 1999 . 10037728 . 10.1074/jbc.274.10.6374 . etal. free .
• Aminoff M, Carter JE, Chadwick RB . Mutations in CUBN, encoding the intrinsic factor-vitamin B₁₂ receptor, cubilin, cause hereditary megaloblastic anaemia 1. . Nat. Genet. . 21 . 3 . 309–13 . 1999 . 10080186 . 10.1038/6831 . 21836060 . etal.
• Kozyraki R, Fyfe J, Kristiansen M . The intrinsic factor-vitamin B₁₂ receptor, cubilin, is a high-affinity apolipoprotein A-I receptor facilitating endocytosis of high-density lipoprotein. . Nat. Med. . 5 . 6 . 656–61 . 1999 . 10371504 . 10.1038/9504 . 9392624 . etal.
• Xu D, Kozyraki R, Newman TC, Fyfe JC . Genetic evidence of an accessory activity required specifically for cubilin brush-border expression and intrinsic factor-cobalamin absorption. . Blood . 94 . 10 . 3604–6 . 1999 . 10552972 . 10.1182/blood.V94.10.3604.422k22_3604_3606.
• Birn H, Fyfe JC, Jacobsen C . Cubilin is an albumin binding protein important for renal tubular albumin reabsorption. . J. Clin. Invest. . 105 . 10 . 1353–61 . 2000 . 10811843 . 10.1172/JCI8862 . 315466 . etal.
• Kristiansen M, Aminoff M, Jacobsen C . Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin. . Blood . 96 . 2 . 405–9 . 2000 . 10887099 . 10.1182/blood.V96.2.405 . etal.
• Yammani RR, Seetharam S, Seetharam B . Cubilin and megalin expression and their interaction in the rat intestine: effect of thyroidectomy. . Am. J. Physiol. Endocrinol. Metab. . 281 . 5 . E900–7 . 2001 . 11595644 . 10.1152/ajpendo.2001.281.5.E900. 1438500 .
• Kozyraki R, Fyfe J, Verroust PJ . Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia. . Proc. Natl. Acad. Sci. U.S.A. . 98 . 22 . 12491–6 . 2001 . 11606717 . 10.1073/pnas.211291398 . 60081 . 2001PNAS...9812491K . etal. free .
• Nykjaer A, Fyfe JC, Kozyraki R . Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). . Proc. Natl. Acad. Sci. U.S.A. . 98 . 24 . 13895–900 . 2002 . 11717447 . 10.1073/pnas.241516998 . 61138 . etal. free .
• Fedosov SN, Berglund L, Fedosova NU . Comparative analysis of cobalamin binding kinetics and ligand protection for intrinsic factor, transcobalamin, and haptocorrin. . J. Biol. Chem. . 277 . 12 . 9989–96 . 2002 . 11788601 . 10.1074/jbc.M111399200 . etal. free .
• Crider-Pirkle S, Billingsley P, Faust C . Cubilin, a binding partner for galectin-3 in the murine utero-placental complex. . J. Biol. Chem. . 277 . 18 . 15904–12 . 2002 . 11856751 . 10.1074/jbc.M200331200 . etal. free .
• Wahlstedt-Fröberg V, Pettersson T, Aminoff M . Proteinuria in cubilin-deficient patients with selective vitamin B₁₂ malabsorption. . Pediatr. Nephrol. . 18 . 5 . 417–21 . 2004 . 12687456 . 10.1007/s00467-003-1128-y . 10669019 . etal.
• Smith. BT . Mussell, JC . Fleming, PA . Barth, JL . Spyropoulos, DD . Cooley, MA . Drake, CJ . Argraves, WS. Targeted disruption of cubilin reveals essential developmental roles in the structure and function of endoderm and in somite formation.. BMC Developmental Biology. 2006. 6. 30. 16787536. 10.1186/1471-213X-6-30. 1533814 . free .

Notes and References

1. Kozyraki R, Kristiansen M, Silahtaroglu A, Hansen C, Jacobsen C, Tommerup N, Verroust PJ, Moestrup SK . The human intrinsic factor-vitamin B₁₂ receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region . Blood . 91 . 10 . 3593–600 . Jun 1998 . 9572993 . 10.1182/blood.V91.10.3593. free .
2. Moestrup SK, Kozyraki R, Kristiansen M, Kaysen JH, Rasmussen HH, Brault D, Pontillon F, Goda FO, Christensen EI, Hammond TG, Verroust PJ . The intrinsic factor-vitamin B₁₂ receptor and target of teratogenic antibodies is a megalin-binding peripheral membrane protein with homology to developmental proteins . J Biol Chem . 273 . 9 . 5235–42 . Mar 1998 . 9478979 . 10.1074/jbc.273.9.5235 . free .
3. Web site: Entrez Gene: CUBN cubilin (intrinsic factor-cobalamin receptor).
4. Uhlén. Mathias. Fagerberg. Linn. Hallström. Björn M.. Lindskog. Cecilia. Oksvold. Per. Mardinoglu. Adil. Sivertsson. Åsa. Kampf. Caroline. Sjöstedt. Evelina. 2015-01-23. Tissue-based map of the human proteome. Science. en. 347. 6220. 1260419. 10.1126/science.1260419. 0036-8075. 25613900. 802377.
5. Web site: Tissue expression of CUBN - Summary - The Human Protein Atlas. www.proteinatlas.org. 2017-09-06.
6. Gremel. Gabriela. Djureinovic. Dijana. Niinivirta. Marjut. Laird. Alexander. Ljungqvist. Oscar. Johannesson. Henrik. Bergman. Julia. Edqvist. Per-Henrik. Navani. Sanjay. 2017-01-04. A systematic search strategy identifies cubilin as independent prognostic marker for renal cell carcinoma. BMC Cancer. En. 17. 1. 9. 10.1186/s12885-016-3030-6. 28052770. 5215231. 1471-2407 . free .
7. Uhlen. Mathias. Zhang. Cheng. Lee. Sunjae. Sjöstedt. Evelina. Fagerberg. Linn. Bidkhori. Gholamreza. Benfeitas. Rui. Arif. Muhammad. Liu. Zhengtao. 2017-08-18. A pathology atlas of the human cancer transcriptome. Science. en. 357. 6352. eaan2507. 10.1126/science.aan2507. 0036-8075. 28818916. free.
8. Web site: Expression of CUBN in renal cancer - The Human Protein Atlas. www.proteinatlas.org. 2017-09-06.