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Dynamic Function of DPMS Is Essential for Angiogenesis and Cancer Progression

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Biochemical and Biophysical Roles of Cell Surface Molecules

Part of the book series: Advances in Experimental Medicine and Biology ((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.

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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).

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Authors and Affiliations

  1. Department of Biochemistry, School of Medicine, University of Puerto Rico, San Juan, PR, USA

    Zhenbo Zhang, Jesús E. Serrano-Negrón, Juan A. Martínez & Dipak K. Banerjee

  2. Department of Natural Sciences & Mathematics, Interamerican University of Puerto Rico, Bayamón, PR, USA

    Jesús E. Serrano-Negrón

  3. Universidad Central del Caribe, Department of Anatomy and Cell Biology, School of Medicine, Universidad Central del Caribe, Bayamón, PR, USA

    Krishna Baksi

  4. Institute of Functional Nanomaterials, University of Puerto Rico, San Juan, PR, USA

    Dipak K. Banerjee

  5. Toronto Western Research Institute, University Health Network, Toronto, ON, Canada

    Zhenbo Zhang

  6. Ology Bioservices, Alachua, FL, USA

    Juan A. Martínez

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  1. Zhenbo Zhang
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  2. Jesús E. Serrano-Negrón
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  3. Juan A. Martínez
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  4. Krishna Baksi
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  5. Dipak K. Banerjee
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Correspondence to Dipak K. Banerjee .

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Editors and Affiliations

  1. Centre for Protein Science, Design and Engineering, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Mohali, Punjab, India

    Kausik Chattopadhyay

  2. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA

    Subhash C. Basu

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Zhang, Z., Serrano-Negrón, J.E., Martínez, J.A., Baksi, K., Banerjee, D.K. (2018). Dynamic Function of DPMS Is Essential for Angiogenesis and Cancer Progression. In: Chattopadhyay, K., Basu, S. (eds) Biochemical and Biophysical Roles of Cell Surface Molecules. Advances in Experimental Medicine and Biology, vol 1112. Springer, Singapore. https://doi.org/10.1007/978-981-13-3065-0_16

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