RPN2 explained

Dolichyl-diphosphooligosaccharide—protein glycosyltransferase subunit 2, also called ribophorin ǁ is an enzyme that in humans is encoded by the RPN2 gene.^[1]

Function

This gene encodes a type I integral ribophorin membrane protein found only in the rough endoplasmic reticulum. The encoded protein is part of an N-oligosaccharyl transferase complex that links high mannose oligosaccharides to asparagine residues found in the Asn-X-Ser/Thr consensus motif of nascent polypeptide chains. This protein is similar in sequence to the yeast oligosaccharyl transferase subunit SWP1. RPN2 has been demonstrated to be a prognostic marker of human cancer, and may be a potential target of clinical importance.

Structure

Gene

The RPN2 gene lies on the chromosome location of 20q11.23 and consists of 19 exons.

Protein

RPN2 consists of 631 amino acid residues and weighs 69284Da.

Function

RPN2 is a unique integral glycoprotein in rough ER membrane that is involved in translocation and the maintenance of the structural uniqueness of the rough ER. It is also an essential subunit of N-oligosaccharyl transferase complex that conjugates high mannose oligosaccharides to asparagine residues in the N-X-S/T consensus motif of nascent polypeptide chains.^{[2] [3] [4] [5]} RPN2 regulates the glycosylation of multi-drug resistance, and thus its interference could decrease the membrane localization of P-glycoprotein by reducing its glycosylation status and restored the sensitivity to docetaxel.^[6]

Clinical significance

RPN2 has been demonstrated to be a prognostic marker of human cancer. RPN2 is highly expressed in breast cancer stem cells and is associated with tumor metastasis. Recent study has shown that its expression is correlated with clinically aggressive features of breast cancer, implying a possible application in personalized medicine.^[7] RPN2 silencing has been reported to repress tumorigenicity and to sensitize the tumors to cisplatin treatment, which led to the longer survival of NSCLC-bearing mice, suggesting that RPN2 may represent a promising new target for RNAi-based medicine against NSCLC. Similar potential application has also been shown in osteosarcoma, esophageal squamous cell carcinoma and colorectal cancer.^{[8] [9] [10]} RPN2 is also reported to be one of the prothrombin-binding proteins on monocyte surfaces, suggesting that its involvement in the pathophysiology of thrombosis in patients with APS.^[11]

Interactions

P53

tetraspanin CD63 ^[12]

prothrombin

Further reading

• Stoffel M, Xiang K, Bell GI . Dinucleotide repeat polymorphism at the human ribophorin II locus (RPN2) on chromosome 20q . Human Molecular Genetics . 1 . 8 . 656 . November 1992 . 1301181 . 10.1093/hmg/1.8.656 .
• Löffler C, Rao VV, Hansmann I . Mapping of the ribophorin II (RPN II) gene to human chromosome 20q12-q13.1 by in-situ hybridization . Human Genetics . 87 . 2 . 221–2 . June 1991 . 2066112 . 10.1007/BF00204188 . 26258810 .
• Kumar V, Heinemann FS, Ozols J . Interleukin-2 induces N-glycosylation in T-cells: characterization of human lymphocyte oligosaccharyltransferase . Biochemical and Biophysical Research Communications . 247 . 2 . 524–9 . June 1998 . 9642163 . 10.1006/bbrc.1998.8780 .
• Fu J, Kreibich G . Retention of subunits of the oligosaccharyltransferase complex in the endoplasmic reticulum . The Journal of Biological Chemistry . 275 . 6 . 3984–90 . February 2000 . 10660554 . 10.1074/jbc.275.6.3984 . free .
• Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J . Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides . Nature Biotechnology . 21 . 5 . 566–9 . May 2003 . 12665801 . 10.1038/nbt810 . 23783563 .
• Kelleher DJ, Karaoglu D, Mandon EC, Gilmore R . Oligosaccharyltransferase isoforms that contain different catalytic STT3 subunits have distinct enzymatic properties . Molecular Cell . 12 . 1 . 101–11 . July 2003 . 12887896 . 10.1016/S1097-2765(03)00243-0 . free .
• Shibatani T, David LL, McCormack AL, Frueh K, Skach WR . Proteomic analysis of mammalian oligosaccharyltransferase reveals multiple subcomplexes that contain Sec61, TRAP, and two potential new subunits . Biochemistry . 44 . 16 . 5982–92 . April 2005 . 15835887 . 10.1021/bi047328f .
• Tu LC, Yan X, Hood L, Lin B . Proteomics analysis of the interactome of N-myc downstream regulated gene 1 and its interactions with the androgen response program in prostate cancer cells . Molecular & Cellular Proteomics . 6 . 4 . 575–88 . April 2007 . 17220478 . 10.1074/mcp.M600249-MCP200 . free.

Notes and References

1. Web site: Entrez Gene: RPN2 ribophorin II.
2. Kelleher DJ, Kreibich G, Gilmore R . Oligosaccharyltransferase activity is associated with a protein complex composed of ribophorins I and II and a 48 kd protein . Cell . 69 . 1 . 55–65 . April 1992 . 1555242 . 10.1016/0092-8674(92)90118-v. 46304250 .
3. Kelleher DJ, Gilmore R . An evolving view of the eukaryotic oligosaccharyltransferase . Glycobiology . 16 . 4 . 47R–62R . April 2006 . 16317064 . 10.1093/glycob/cwj066 . free .
4. Crimaudo C, Hortsch M, Gausepohl H, Meyer DI . Human ribophorins I and II: the primary structure and membrane topology of two highly conserved rough endoplasmic reticulum-specific glycoproteins . The EMBO Journal . 6 . 1 . 75–82 . January 1987 . 3034581 . 553359 . 10.1002/j.1460-2075.1987.tb04721.x .
5. Yuan TM, Liang RY, Chueh PJ, Chuang SM . Role of ribophorin II in the response to anticancer drugs in gastric cancer cell lines . Oncology Letters . 9 . 4 . 1861–1868 . April 2015 . 25789057 . 4356382 . 10.3892/ol.2015.2900 .
6. Fujita Y, Yagishita S, Takeshita F, Yamamoto Y, Kuwano K, Ochiya T . Prognostic and therapeutic impact of RPN2-mediated tumor malignancy in non-small-cell lung cancer . Oncotarget . 6 . 5 . 3335–45 . February 2015 . 25595901 . 4413657 . 10.18632/oncotarget.2793 .
7. Ono M, Tsuda H, Kobayashi T, Takeshita F, Takahashi RU, Tamura K, Akashi-Tanaka S, Moriya T, Yamasaki T, Kinoshita T, Yamamoto J, Fujiwara Y, Ochiya T . The expression and clinical significance of ribophorin II (RPN2) in human breast cancer . Pathology International . 65 . 6 . 301–8 . June 2015 . 25881688 . 10.1111/pin.12297 . 36249480 .
8. Fujiwara T, Takahashi RU, Kosaka N, Nezu Y, Kawai A, Ozaki T, Ochiya T . RPN2 Gene Confers Osteosarcoma Cell Malignant Phenotypes and Determines Clinical Prognosis . Molecular Therapy: Nucleic Acids . 3 . e189 . September 2014 . 9 . 25181275 . 4222647 . 10.1038/mtna.2014.35 .
9. Kurashige J, Watanabe M, Iwatsuki M, Kinoshita K, Saito S, Nagai Y, Ishimoto T, Baba Y, Mimori K, Baba H . RPN2 expression predicts response to docetaxel in oesophageal squamous cell carcinoma . British Journal of Cancer . 107 . 8 . 1233–8 . October 2012 . 22955852 . 3494434 . 10.1038/bjc.2012.396 .
10. Zhang J, Yan B, Späth SS, Qun H, Cornelius S, Guan D, Shao J, Hagiwara K, Van Waes C, Chen Z, Su X, Bi Y . Integrated transcriptional profiling and genomic analyses reveal RPN2 and HMGB1 as promising biomarkers in colorectal cancer . Cell & Bioscience . 5 . 53 . 2015-01-01 . 26388988 . 4574027 . 10.1186/s13578-015-0043-9 . free .
11. Fujieda Y, Amengual O, Matsumoto M, Kuroki K, Takahashi H, Kono M, Kurita T, Otomo K, Kato M, Oku K, Bohgaki T, Horita T, Yasuda S, Maenaka K, Hatakeyama S, Nakayama KI, Atsumi T . Ribophorin II is involved in the tissue factor expression mediated by phosphatidylserine-dependent antiprothrombin antibody on monocytes . Rheumatology . 55 . 6 . 1117–26 . June 2016 . 26895716 . 10.1093/rheumatology/kew005 . free .
12. Tominaga N, Hagiwara K, Kosaka N, Honma K, Nakagama H, Ochiya T . RPN2-mediated glycosylation of tetraspanin CD63 regulates breast cancer cell malignancy . Molecular Cancer . 13 . 134 . May 2014 . 24884960 . 4070641 . 10.1186/1476-4598-13-134 . free .