Advertisement

Dynamic Function of DPMS Is Essential for Angiogenesis and Cancer Progression

  • Zhenbo Zhang
  • Jesús E. Serrano-Negrón
  • Juan A. Martínez
  • Krishna Baksi
  • Dipak K. Banerjee
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1112)

Abstract

Dolichol phosphate mannose synthase (DPMS) is an inverting GT-A-folded enzyme and classified as GT2 by CAZy. DPMS sequence carries a metal-binding DXD motif, a PKA motif, and a variable number of hydrophobic domains. Human and bovine DPMS possess a single transmembrane domain, whereas that from S. cerevisiae and A. thaliana carry multiple transmembrane domains and are superimposable. The catalytic activity of DPMS is documented in all spheres of life, and the 32kDa protein is uniquely regulated by protein phosphorylation. Intracellular activation of DPMS by cAMP signaling is truly due to the activation of the enzyme and not due to increased Dol-P level. The sequence of DPMS in some species also carries a protein N-glycosylation motif (Asn-X-Ser/Thr). Apart from participating in N-glycan biosynthesis, DPMS is essential for the synthesis of GPI anchor as well as for O- and C-mannosylation of proteins. Because of the dynamic nature, DPMS actively participates in cellular proliferation enhancing angiogenesis and breast tumor progression. In fact, overexpression of DPMS in capillary endothelial cells supports increased N-glycosylation, cellular proliferation, and enhanced chemotactic activity. These are expected to be completely absent in congenital disorders of glycosylation (CDGs) due to the silence of DPMS catalytic activity. DPMS has also been found to be involved in the cross talk with N-acetylglucosaminyl 1-phosphate transferase (GPT). Inhibition of GPT with tunicamycin downregulates the DPMS catalytic activity quantitatively. The result is impairment of surface N-glycan expression, inhibition of angiogenesis, proliferation of human breast cancer cells, and induction of apoptosis. Interestingly, nano-formulated tunicamycin is three times more potent in inhibiting the cell cycle progression than the native tunicamycin and is supported by downregulation of the ratio of phospho-p53 to total-p53 as well as phospho-Rb to total Rb. DPMS expression is also reduced significantly. However, nano-formulated tunicamycin does not induce apoptosis. We, therefore, conclude that DPMS could become a novel target for developing glycotherapy treating breast tumor in the clinic.

Keywords

Angiogenesis Asparagine-linked glycoprotein Breast cancer Carbohydrate-active enzyme Dolichol phosphate mannose synthase Endoplasmic reticulum Glycosyltransferase Phosphoprotein Protein N-glycosylation Unfolded protein response 

Notes

Acknowledgment

This work is partly supported by funds from the Office of the Dean, School of Medicine, University of Puerto Rico, and grants from the Department of Defense DAMD17-03-1-0754, the National Institutes of Health NIH U54-CA096297, Susan G. Komen for the Cure BCTR0600582, the National Science Foundation NSF EPS-1002410 (DKB), and the National Institutes of Health NIH/NIMHD 2G12MD007583 (KB).

References

  1. Baksi K, Tavárez-Pagán JJ, Martínez JA, Banerjee DK (2008) Unique structural motif supports mannosylphospho dolichol synthase: an important angiogenesis regulator. Curr Drug Targets 9:262–271CrossRefGoogle Scholar
  2. Banerjee DK (1988) Microenvironment of endothelial cell growth and regulation of protein N-glycosylation. Indian J Biochem Biophys 25:8–13PubMedGoogle Scholar
  3. Banerjee DK (1989) Amphomycin inhibits mannosylphosphoryldolichol synthesis by forming a complex with dolichylmonophosphate. J Biol Chem 264:2024–2028PubMedGoogle Scholar
  4. Banerjee DK (1994) A recent approach to the study of dolichyl monophosphate topology in the rough endoplasmic reticulum. Acta Biochim Pol 41:275–280PubMedGoogle Scholar
  5. Banerjee DK (2012) N-glycans in cell survival and death: cross-talk between glycosyltransferases. Biochim Biophys Acta 1820:1338–1346CrossRefGoogle Scholar
  6. Banerjee DK, Scher MG, Waechter CJ (1981) Amphomycin: effect of the lipopeptide antibiotic on the glycosylation and extraction of dolichyl monophosphate in calf brain membranes. Biochemistry 20:1561–1568CrossRefGoogle Scholar
  7. Banerjee DK, Kousvelari EE, Baum BJ (1985) beta-Adrenergic activation of glycosyltransferases in the dolichylmonophosphate-linked pathway of protein N-glycosylation. Biochem Biophys Res Commun 126:123–129CrossRefGoogle Scholar
  8. Banerjee DK, Kousvelari EE, Baum BJ (1987) cAMP-mediated protein phosphorylation of microsomal membranes increases mannosylphospho dolichol synthase activity. Proc Natl Acad Sci (USA) 84:6389–6393CrossRefGoogle Scholar
  9. Banerjee DK, Tavárez JJ, Oliveira CM (1992) Expression of blood clotting factor VIII:C gene in capillary endothelial cells. FEBS Lett 306:33–37CrossRefGoogle Scholar
  10. Banerjee DK, DaSilva JJ, Bigio B (1999) Mannosylphosphodolichol synthase activity is associated with a 32 kDa phosphoprotein. Biosci Rep 19:169–177CrossRefGoogle Scholar
  11. Banerjee A, Lang JY, Hung MC, Sengupta K, Banerjee SK, Baksi K, Banerjee DK (2011a) Unfolded protein response is required in nu/nu mice microvasculature for treating breast tumor with tunicamycin. J Biol Chem 286:29127–29138CrossRefGoogle Scholar
  12. Banerjee DK, Oliveira CM, Tavárez JJ, Katiyar VN, Saha S, Martínez JA, Banerjee A, Sánchez A, Baksi K (2011b) Importance of a factor VIIIc-like glycoprotein expressed in capillary endothelial cells (eFactor VIIIc) in angiogenesis. Adv Exp Med Biol 705:453–464CrossRefGoogle Scholar
  13. Banerjee A, Johnson KT, Banerjee IA, Banerjee DK (2013) Nanoformulation enhances anti-angiogenic efficacy of tunicamycin. Transl Cancer Res 2:240–255Google Scholar
  14. Banerjee A, Martinez JA, Longas MO, Zhang Z, Santiago J, Baksi K, Banerjee DK (2015) N-acetylglucosaminyl 1-phosphate transferase: an excellent target for developing new generation breast cancer therapeutic. Adv Exp Med Biol 842:355–374CrossRefGoogle Scholar
  15. Banerjee DK, Zhang Z, Baksi K, Serrano-Negrón JE (2017) Dolichol phosphate mannose synthase: A Glycosyltransferase with Unity and molecular diversities. Glycoconj J 34:467–479CrossRefGoogle Scholar
  16. Bujnicki JM, Elofsson A, Fischer D, Rychlewski L (2001) Structure prediction meta server. Bioinformatics 17:750–751CrossRefGoogle Scholar
  17. Calo D, Kaminski L, Eichler J (2010) Protein glycosylation in Archaea: sweet and extreme. Glycobiology 20:1065–1076CrossRefGoogle Scholar
  18. Fay PJ (1999) Regulation of factor VIIIa in the intrinsic factor Xase. Thromb Haemost 82:193–200CrossRefGoogle Scholar
  19. Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6:273–286CrossRefGoogle Scholar
  20. Gandini R, Reichenbach T, Tan T, Divne C (2017) Structural basis for dolichylphosphate mannose biosynthesis. Nat Commun 8:1–12CrossRefGoogle Scholar
  21. Gasteiger E, Hoogland C, Gattiker A, Duvaud S, Wilkins MR, Appel RD, Bairoch A (2005) Protein identification and analysis tools on the ExPASy server. In: Walker JM (ed) The proteomics protocols handbook. Humana Press, Totowa, pp 571–607CrossRefGoogle Scholar
  22. Gastl G, Hermann T, Steurer M, Zmija J, Gunsilius E, Unger C, Kraft A (1997) Angiogenesis as a target for tumor treatment. Oncology 54:177–178CrossRefGoogle Scholar
  23. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674CrossRefGoogle Scholar
  24. Helenius A, Aebi M (2004) Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem 73:1019–1049CrossRefGoogle Scholar
  25. Kane WH, Davie EW (1988) Blood coagulation factors V and VIII: structural and functional similarities and their relationship to hemorrhagic and thrombotic disorders. Blood 71:539–555PubMedGoogle Scholar
  26. Kean EL (1982) Activation by dolichol phosphate-mannose of the biosynthesis of N-acetyl- glucosaminylpyrophosphoryl polyprenols by the retina. J Biol Chem 257:7952–7954PubMedGoogle Scholar
  27. Kornfeld R, Kornfeld S (1985) Assembly of asparagine-linked oligosaccharides. Annu Rev Biochem 54:6631–6636CrossRefGoogle Scholar
  28. Kyte J. Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157:105–132CrossRefGoogle Scholar
  29. Lamani E, Mewbourne RB, Fletcher DS, Maltsev SD, Danilov LL, Veselovsky VV, Lozanova AV, Grigorieva NY, Pinsker OA, Xing J, Forsee WT, Cheung HC, Schutzbach JS, Shibaev VN, Jedrzejas MJ (2006) Structural studies and mechanism of Saccharomyces cerevisiae dolichyl-phosphatemannose synthase: insights into the initial step of synthesis of dolichyl-phosphate-linked oligosaccharide chains in membranes of endoplasmic reticulum. Glycobiology 16:666–678CrossRefGoogle Scholar
  30. Lenting PJ, van Mourik JA, Mertens K (1998) The life cycle of coagulation factor VIII in view of its structure and function. Blood 92:3983–3996PubMedGoogle Scholar
  31. Martinez JA (2002) Angiogenesis and Glycosylation: interplay between dolichol cycle and cell cycle. In: Ph.D. thesis, University of Puerto Rico School of Medicine, San Juan, PR, pp 1–233Google Scholar
  32. Nguyen M, Folkman J, Bischoff J (1992) 1-Deoxymannojirimycin inhibits capillary tube formation in vitro. Analysis of N-linked oligosaccharides in bovine capillary endothelial cells. J Biol Chem 267:26157–26165PubMedGoogle Scholar
  33. Nguyen M, Strubel NA, Bischoff J (1993) A role for sialyl Lewis-X/A glycoconjugates in capillary morphogenesis. Nature 365:267–269CrossRefGoogle Scholar
  34. Pili R, Chang J, Partis RA, Mueller RA, Chrest FJ, Passaniti A (1995) The alpha-glucosidase I inhibitor castanospermine alters endothelial cell glycosylation, prevents angiogenesis, and inhibits tumor growth. Cancer Res 55:2920–2926PubMedGoogle Scholar
  35. Schneider BP, Miller KD (2005) Angiogenesis of breast cancer. J Clin Oncol 23:1782–1790CrossRefGoogle Scholar
  36. Sinhoara H, Maruyama T (1973) Evolution of glycoproteins as judged by the frequency of occurrence of the tripeptides Asn-X-Ser and Asn-X-Thr in proteins. J Mol Evol 2:117–122CrossRefGoogle Scholar
  37. Szymanski CM, Wren BW (2005) Protein glycosylation in bacterial mucosal pathogens. Nat Rev Microbiol 3:225–237CrossRefGoogle Scholar
  38. Tarbouriech N, Charnock SJ, Davies GJ (2001) Three-dimensional structures of the Mn and Mg dTDP complexes of the family GT-2 glycosyltransferase SpsA: a comparison with related NDP-sugar glycosyltransferases. J Mol Biol 314:655–661CrossRefGoogle Scholar
  39. Uhr JW, Scheuermann RH, Street NE, Vitetta ES (1997) Cancer dormancy: opportunities for new therapeutic approaches. Nat Med 3:505–509CrossRefGoogle Scholar
  40. Zhang Z, Banerjee A, Baksi K, Banerjee DK (2010) Mannosylphosphodolichol synthase overexpression supports angiogenesis. Biocatal Biotransformation 28:90–98CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Zhenbo Zhang
    • 1
    • 5
  • Jesús E. Serrano-Negrón
    • 1
    • 2
  • Juan A. Martínez
    • 1
    • 6
  • Krishna Baksi
    • 3
  • Dipak K. Banerjee
    • 1
    • 4
  1. 1.Department of Biochemistry, School of MedicineUniversity of Puerto RicoSan JuanUSA
  2. 2.Department of Natural Sciences & MathematicsInteramerican University of Puerto RicoBayamónUSA
  3. 3.Universidad Central del Caribe, Department of Anatomy and Cell BiologySchool of Medicine, Universidad Central del CaribeBayamónUSA
  4. 4.Institute of Functional NanomaterialsUniversity of Puerto RicoSan JuanUSA
  5. 5.Toronto Western Research InstituteUniversity Health NetworkTorontoCanada
  6. 6.Ology BioservicesAlachuaUSA

Personalised recommendations