Professor, Biochemistry and Molecular Biology
Phone: 402-559-5776 (Office)
Ph.D., Case Western Reserve University, 1975
Student research opportunities in my lab:
High school students
Primary Research/Clinical Interests/Expertise:
Regulation of mucin glycan biosynthesis in lung diseases and cancer metastasis
Golgi structure and function: Golgi targeting and retention, and recycling of glycosyltransferases
Mechanism of stress-induced Golgi fragmentation
Mucin-type carbohydrates are linked covalently through N-acetylgalactosamine to serine/threonine on the peptide backbone of many glycoproteins. They are abundantly present in secreted and membrane-bound mucins, and the primary determinants of the functions of these mucins. Mucin-type carbohydrates constitute 80-90% of the secreted mucins, which help trap airborne and ingested pathogens. These two chemical properties allow the secreted mucins to protect the underlying epithelium by hydration of the mucus and clearance the pathogens. Decrease in carbohydrate content and heterogeneous structure can cause chronic inflammation and diseases, such as colitis and colon cancer. Excessive secretion of mucins coupled with defective clearance mechanism would result in obstructive lung diseases. Mucin-type carbohydrate also make up a significant portion of the membrane-bound mucins. They serve as the selectin ligands to direct leukocyte trafficking. Loss or uncontrolled production of these selectin ligands can lead to compromised immune functions. Production of these ligands in cancer cells facilitate metastasis. Thus, we are interested in understanding how the synthesis of mucin-type glycans is regulated.
Recently, we began to focus on the mechanisms of Golgi targeting and retention, and recycling of glycosyltransferases because mucin-type glycans are synthesized exclusively in the Golgi apparatus. Further, synthesis of conjugated glycans is a template-independent process and catalyzed by glycosyltransferases localized to different Golgi compartments according to the biosynthetic steps they participate in. The enzymes that synthesize the carbohydrate structures near the reducing end are in the cis-Golgi and those that synthesize the non-reducing terminal structures are in the trans-Golgi. We have identified GM130-GRASP65, GM130-Giantin, and Giantin as the Golgi targeting sites for glycosyltransferases in a glycosyltransferase-specific fashion. Also, we have identified Golgi phosphoprotein 3 as the protein that helps retain C2GnT-1/L in the Golgi by binding to the cytoplasmic tail of this enzyme. As such, Golgi phosphoprotein 3, an oncogene protein, controls the metastatic properties of cancer cells by controlling the synthesis of a selectin ligand, core 2-associated sialyl Lewis x. Also, we have shown that recycling of Golgi glycosyltransferases is mediated by non-muscle myosin IIA via its interaction with the cytoplasmic tails of glycosyltransferases. This interaction is also responsible for Golgi fragmentation induced by stress, including heat shock, inhibition of heat shock proteins, alcohol abuse, treatment with brefeldin A, cancer etc.
- Determination of Golgi targeting,retention, and recycling mechanisms of glycosyltransferases
- Determination of the alcohol effect on mucus defense in the lungs.
- Identification of the glycosyltransferases that work on secreted and membrane-bound mucins
- Regulation of mucin glycans involved in cancer progression and metastasis
Petrosyan A, Cheng P-W, Clemens D L and Casey C A. Downregulation of the small GTPase SAR1A: a key event underlying alcohol-induced Golgi fragmentation in hepatocytes. Sci. Rep. 5:17127, 2015. Doi:10.1038/srep17127 (PMID:26607390)(PMCID:4660820) PWC
Chachadi VB, Bhat G, and Cheng P-W. Glycosyltransferases involved in the synthesis of MUC-associated metastasis-promoting selectin ligands. Glycobiology (In press) Published online May 14, 2015. doi: 10.1093/glycob/cwv030
Petrosyan A, Ali M, and Cheng P-W. Keratin 1 plays a critical role in Golgi localization of Core 2 N-acetylglucosaminyltransferase M via interaction with its cytoplasmic tail. J Biol Chem 290(10):6256-69, 2015. Published online Jan. 20, 2015 Doi: 10.1074/jbc.M114.618702. (PMID:25605727)
Petrosyan A, Holzapfel MS, Muirhead DE and Cheng P-W. Restoration of compact Golgi morphology in advanced prostate cancer enhances susceptibility to galectin 1-induced apoptosis by modifying mucin O-glycan synthesis. Mol Cancer Res 12(12): 1704-16, 2014. published online First August 1, 2014; doi:10.1158/1541-7786. MCR-14-0291-T. (PMID:25086069) (PMCID: 4272641)
Petrosyan A and Cheng P-W. Golgi fragmentation induced by heat shock or inhibition of heat shock proteins is mediated by non-muscle myosin IIA via its interaction with glycosyltransferases. Cell Stress & Chaperones 19(2):241-54, 2014. 10.1007/s12192-013-0450-y. ISSN:1355-8145.PMID:23990450 (PMCID: 3933620)
Chachadi V, Ali MF, and Cheng P-W. Prostatic cell-specific regulation of the synthesis of MUC1-associated sialyl Lewis a. PLoS One. 2013 8(2):e57416. doi:10.1371/journal pone.0057416.
Petrosyan A and Cheng P-W. A non-enzymatic function of Golgi glycosyltransferases: mediation of Golgi fragmentation by interaction with non-muscle myosin IIA. Glycobiology 23(6):690-908, 2013. doi:101093/glycob/ewt009.
Ali MF, Chachadi VB, Petrosyan A, and Cheng P-W. Golgi phosphoprotein 3 determines cell binding properties under dynamic flow by controlling golgi localization of Core 2 N-acetylglucosaminyltransferase 1. J. Biol. Chem. 2012 Nov 16;287(47):39564-77. doi: 10.1074/jbc.M112.346528. Epub 2012 Oct 1.
Petrosyan A, Ali M, and Cheng P-W. Glycosyltransferase-specific golgi targeting mechanisms. J. Biol. Chem. 2012 Nov 2; 287 (45):37621-7. doi: 10.1074/jbc.C112-403006. Epub 2012 Sep 17.
Gao Y, Chachadi VB, Cheng P-W, and Brockhausen I. Glycosyltransferase activities and mRNA expression in human prostate cancer cell lines. Glycoconjugate J. 29(7):525-37, 2012. doi: 10.1007/s10719-012-9428-8. Epub 2012 July 28.
Petrosyan A, Ali MF, Verma SK, Cheng H, and Cheng P-W. Non-muscle myosin IIA transports a Golgi enzyme to the ER by binding to its cytoplasmic tail. Int. J. Biochem. Cell Biol. 44:1153-65, 2012. doi: 10.1016/j.biocel.2012.04.004.
Arpke RW and Cheng P-W. Characterization of human serum albumin-facilitated lipofection gene delivery strategy. J. Cell Sci. Ther. 2(3):108, 2011 doi:10.4272/2157-7013. 1000108.
Radhakrishnan P, Chachadi V, Lin M-F, Singh R, Kannagi R and Cheng P-W. TNFα enhances the motility and invasiveness of prostatic cancer cells by stimulating the expression of selective glycosyl- and sulfotransferase genes involved in the synthesis of selectin ligands. Biochem. Biophys. Res. Commun. 409:436-441, 2011. doi: 10.1016/j.bbrc.2011.05.019.
Chachadi VB, Cheng H, Klinkebiel D, Christman JK, and Cheng P-W. 5-Aza-2’-deoxycytidine Increases Sialyl Lewis X on MUC1 by stimulating β-Galactoside α2,3-Sialyltransferase 6 Gene. Int. J. Biochem. Cell Biol. 43(4): 586–593, 2011. DOI:10.1016/j.biocell. 2010.12.015.
Kumar S, Rajendran M, Alam SM, Lin F-F, Cheng P-W, and Lin M-F. Steroids up-regulate p66Shc longevity protein in growth regulation by inhibiting its ubiquitination. PLoS ONE 6(1): e15942, 2011.doi:10.1371/ journal.pone.0015942.
Radhakrishnan P, Lin MF, and Cheng PW. Elevated expression of L-selectin ligand in lymph node-derived human prostate cancer cells correlates with increased tumorigenicity. Glycoconjugate J. 26(1):75-81, 2009. DOI: 10.1007/s10719-008-9167-z.
Radhakrishnan P*, Basma H*, Klinkebiel D, Christman J, and Cheng PW. Cell type-specific activation of the cytomegalovirus promoter by dimethyl sulfoxide and 5-aza-2'-deoxycytidine. Int. J. Biochem. Cell. Biol. 40(9):1944-55, 2008. DOI: 10.1016/j.biocel.2008.02.014 (*equal contribution).
Tan S and Cheng PW. Mucin biosynthesis: identification of the cis-regulatory elements of human C2GnT-M gene. Am. J. Respir. Cell and Mol. Biol. 36:737-45, 2007. DOI:10.1165/rcmb.2006-03340C.
Radhakrishnan P, Beum P, and Cheng PW. Butyrate induces the synthesis of sialyl Lewis x carbohydrate epitope in a pancreatic adenocarcinoma cell line. Biochem. Biophys. Res. Commun. 359:457-62, 2007. DOI: 10.1016/j.bbrc.2007.05.165.
Hashimoto M, Tan S, Mori N, Cheng H, and Cheng PW. Mucin biosynthesis: Molecular cloning and expression of mouse mucus-type core 2 β1,6 N-acetylglucosaminyltransferase. Glycobiology 17(9):994-1006, 2007. DOI: 10.1093/glycol/cwm068.
Beum PV, Basma H, Bastola DR, and Cheng PW. Mucin biosynthesis: upregulation of core 2β1,6 N-acetylglucosaminyltransferase by retinoic acid and Th2 cytokines in a human airway epithelial cell line. J. Cell Phyciol-Lung Cell and Mol. Physiol. 288:L1126-L124, 2005. DOI:10.1152/ajplung.00370.2003.
Choi KH, Basma H, Singh J, and Cheng PW. Enhancement of the expression of CMV promoter-controlled glycosyltransferase and β-galactosidase transgenes by butyrate, tricostatin A, and 5-aza-2'-deoxycytidine. Glycoconjugate J. 22:63-9, 2005.
Bandi N, Ayalasomayajula SP, Iwakawa J, Cheng PW, and Kompella UB. Intratracheal budesonide-poly(lactide-co-glycolide) microparticles ameliorate early biochemical changes in benzo(a)pyrene-fed mouse model. J. of Pharm. and Pharmacol. 57:851-60, 2005.
Basma H*, El-Refaey H*, Sgagias MK, Cowan KH, Luo X, and Cheng PW. Bcl-2 antisense enhances cisplatin-induced apoptosis in isogenic MCF-7 breast cancer lines with and without function p53. J. Biomed. Sci. 12:999-1011, 2005. (* Equal contribution) DOI: 10.1007/s11373-005-9025-y.
Choi K, Osorio F, and Cheng PW. Mucin biosynthesis: C2GnT-M gene, tissue-specific expression, and bovine herpes virus-4 homologue. Am. J. Respir. Cell and Mol. Biol. 279:38969-77, 2004. DOI: 10.1165/rcmb.2003-02020C.
Singh J, Khan G, Kinarsky L, Choi K, Cheng H, Wilken J, Bedows E, Sherman S, and Cheng PW. Identification of disulfide bonds among the nine core 2 N-acetyl-glucosaminyltransferase-M cysteines conserved in mucin β6 N-acetylglucosaminyl-transferase family. J. Biol. Chem. 279:38969-77, 2004.
Cheng P-W and Radhakrishnan P. (2010) Mucin glycan branching enzymes: structure, function and gene regulation. In Molecular Immunology of Complex Carbohydrates-3 (Wu, Albert, Ed.) Advances in Experimental Medicine and Biology, Plenum Press, N.Y., N.Y. pp. 511-42.
Sharma NM, Radhakrishnan P, Tan S, and Cheng PW. B3GNT6 (UDP-GlcNAc:βGal β-1,3-N-acetylglucosaminyltransferase 6 (core 3 synthase)). Atlas GenetCytogenet Oncol Haematol. May 2009.
Radhakrishnan P and Cheng PW. GCNT3 (glucosaminyl (N-acetyl) transferase 3, mucin type). Atlas Genet Cytogenet Oncol Haematol. November 2007.
Current Grants and Contracts:
Veteran Administration Merit Award
Title: Golgi localization mechanism of mucin glycosyltransferases
10/1/2011 - 9/30/2015
Nebraska LB506 Tobacco Smoking Research
Title: Mechanism of altered O-glycosylation in prostate cancer
7/1/2014 - 6/30/2015