Cubilin

Cubilin is a protein that in humans is encoded by the CUBN gene.[5][6][7]

CUBN
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3KQ4
Identifiers
Aliases	CUBN, IFCR, MGA1, gp280, cubilin, IGS, IGS1
External IDs	OMIM: 602997 MGI: 1931256 HomoloGene: 37434 GeneCards: CUBN
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10p13 Start 16,823,966 bp[1] End 17,129,811 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2 A1|2 9.86 cM Start 13,276,338 bp[2] End 13,491,813 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • calcium ion binding • protein homodimerization activity • GO:0001948 protein binding • transporter activity • cobalamin binding • metal ion binding • receptor activity • drug binding • channel regulator activity • hemoglobin binding • signaling receptor activity • cargo receptor activity Cellular component • brush border • extrinsic component of external side of plasma membrane • endoplasmic reticulum • clathrin-coated pit • lysosomal membrane • cytoplasm • Golgi apparatus • endosome • apical part of cell • lysosome • lysosomal lumen • membrane • cytosol • extracellular exosome • endocytic vesicle • endosome membrane • cell membrane • apical plasma membrane • brush border membrane • Golgi-associated vesicle • ionotropic glutamate receptor complex • coated vesicle • endocytic vesicle membrane • neuron projection membrane • synapse Biological process • tissue homeostasis • cobalamin transport • lipid metabolism • protein transport • cholesterol metabolic process • vitamin D metabolic process • cobalamin metabolic process • steroid metabolic process • endocytosis • lipoprotein transport • receptor-mediated endocytosis • high-density lipoprotein particle clearance • transport • in utero embryonic development • thigmotaxis • hyperosmotic response • response to nutrient • adult locomotory behavior • response to bacterium • hemoglobin import • regulation of locomotion • cobalamin catabolic process • positive regulation of synaptic transmission, glutamatergic • protein homotrimerization Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	8029	65969
Ensembl	ENSG00000107611	ENSMUSG00000026726
UniProt	O60494	Q9JLB4
RefSeq (mRNA)	NM_001081	NM_001081084
RefSeq (protein)	NP_001072	NP_001074553
Location (UCSC)	Chr 10: 16.82 – 17.13 Mb	Chr 2: 13.28 – 13.49 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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[8], and is essentially only present in the kidneys and small intestine[9]. Mutations in CUBN may play a role in autosomal recessive megaloblastic anemia.[7] A complex of amnionless and cubilin forms the cubam receptor.

Clinical significance

Cubilin is a potential diagnostic and prognostic cancer biomarker for kidney cancer[10]. Based on patient survival data, high levels of cubilin in tumor cells is a favourable prognostic biomarker in renal cell carcinoma[11][12].

References

1. GRCh38: Ensembl release 89: ENSG00000107611 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000026726 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Kozyraki R, Kristiansen M, Silahtaroglu A, Hansen C, Jacobsen C, Tommerup N, Verroust PJ, Moestrup SK (Jun 1998). "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. doi:10.1182/blood.V91.10.3593. PMID 9572993.
6. Moestrup SK, Kozyraki R, Kristiansen M, Kaysen JH, Rasmussen HH, Brault D, Pontillon F, Goda FO, Christensen EI, Hammond TG, Verroust PJ (Mar 1998). "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. doi:10.1074/jbc.273.9.5235. PMID 9478979.
7. "Entrez Gene: CUBN cubilin (intrinsic factor-cobalamin receptor)".
8. 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. 347 (6220): 1260419. doi:10.1126/science.1260419. ISSN 0036-8075. PMID 25613900.
9. "Tissue expression of CUBN - Summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2017-09-06.
10. 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. 17 (1): 9. doi:10.1186/s12885-016-3030-6. ISSN 1471-2407. PMC 5215231. PMID 28052770.
11. 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. 357 (6352): eaan2507. doi:10.1126/science.aan2507. ISSN 0036-8075. PMID 28818916.
12. "Expression of CUBN in renal cancer - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2017-09-06.

Further reading

• Christensen EI, Birn H (2002). "Megalin and cubilin: multifunctional endocytic receptors". Nat. Rev. Mol. Cell Biol. 3 (4): 256–66. doi:10.1038/nrm778. PMID 11994745.
• Bork P, Beckmann G (1993). "The CUB domain. A widespread module in developmentally regulated proteins". J. Mol. Biol. 231 (2): 539–45. doi:10.1006/jmbi.1993.1305. PMID 8510165.
• Birn H, Verroust PJ, Nexo E, et al. (1997). "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. doi:10.1074/jbc.272.42.26497. PMID 9334227.
• Batuman V, Verroust PJ, Navar GL, et al. (1998). "Myeloma light chains are ligands for cubilin (gp280)". Am. J. Physiol. 275 (2 Pt 2): F246–54. doi:10.1152/ajprenal.1998.275.2.F246. PMID 9691015.
• Lindblom A, Quadt N, Marsh T, et al. (1999). "The intrinsic factor-vitamin B₁₂ receptor, cubilin, is assembled into trimers via a coiled-coil alpha-helix". J. Biol. Chem. 274 (10): 6374–80. doi:10.1074/jbc.274.10.6374. PMID 10037728.
• Aminoff M, Carter JE, Chadwick RB, et al. (1999). "Mutations in CUBN, encoding the intrinsic factor-vitamin B₁₂ receptor, cubilin, cause hereditary megaloblastic anaemia 1". Nat. Genet. 21 (3): 309–13. doi:10.1038/6831. PMID 10080186.
• Kozyraki R, Fyfe J, Kristiansen M, et al. (1999). "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. doi:10.1038/9504. PMID 10371504.
• Xu D, Kozyraki R, Newman TC, Fyfe JC (1999). "Genetic evidence of an accessory activity required specifically for cubilin brush-border expression and intrinsic factor-cobalamin absorption". Blood. 94 (10): 3604–6. doi:10.1182/blood.V94.10.3604.422k22_3604_3606. PMID 10552972.
• Birn H, Fyfe JC, Jacobsen C, et al. (2000). "Cubilin is an albumin binding protein important for renal tubular albumin reabsorption". J. Clin. Invest. 105 (10): 1353–61. doi:10.1172/JCI8862. PMC 315466. PMID 10811843.
• Kristiansen M, Aminoff M, Jacobsen C, et al. (2000). "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. doi:10.1182/blood.V96.2.405.014k16_405_409. PMID 10887099.
• Yammani RR, Seetharam S, Seetharam B (2001). "Cubilin and megalin expression and their interaction in the rat intestine: effect of thyroidectomy". Am. J. Physiol. Endocrinol. Metab. 281 (5): E900–7. doi:10.1152/ajpendo.2001.281.5.E900. PMID 11595644.
• Kozyraki R, Fyfe J, Verroust PJ, et al. (2001). "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. doi:10.1073/pnas.211291398. PMC 60081. PMID 11606717.
• Nykjaer A, Fyfe JC, Kozyraki R, et al. (2002). "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. doi:10.1073/pnas.241516998. PMC 61138. PMID 11717447.
• Fedosov SN, Berglund L, Fedosova NU, et al. (2002). "Comparative analysis of cobalamin binding kinetics and ligand protection for intrinsic factor, transcobalamin, and haptocorrin". J. Biol. Chem. 277 (12): 9989–96. doi:10.1074/jbc.M111399200. PMID 11788601.
• Crider-Pirkle S, Billingsley P, Faust C, et al. (2002). "Cubilin, a binding partner for galectin-3 in the murine utero-placental complex". J. Biol. Chem. 277 (18): 15904–12. doi:10.1074/jbc.M200331200. PMID 11856751.
• Wahlstedt-Fröberg V, Pettersson T, Aminoff M, et al. (2004). "Proteinuria in cubilin-deficient patients with selective vitamin B₁₂ malabsorption". Pediatr. Nephrol. 18 (5): 417–21. doi:10.1007/s00467-003-1128-y. PMID 12687456.
• Smith, BT; Mussell, JC; Fleming, PA; Barth, JL; Spyropoulos, DD; Cooley, MA; Drake, CJ; Argraves, WS (2006). "Targeted disruption of cubilin reveals essential developmental roles in the structure and function of endoderm and in somite formation". BMC Developmental Biology. 6: 30. doi:10.1186/1471-213X-6-30. PMC 1533814. PMID 16787536.

External links

• Overview of all the structural information available in the PDB for UniProt: O60494 (Cubilin) at the PDBe-KB.