Dr. James W. Dennis

 

James W. Dennis PhD, FRSC

Canada Research Chair
Senior Investigator & Professor
Departments of Molecular Genetics and
Laboratory Medicine and Pathology
Lunenfeld-Tanenbaum Research Institute
Mount Sinai Hospital
600 University Ave. R988
Toronto, ON. M5G 1X5
Phone: Lab- 416-586-4800 X8268
Office-416-586-8233

  

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Research Interests

Protein N-glycosylation and Golgi remodeling are essential in vertebrates.

The cell membrane is a protective bilayer embedded with glycoproteins that mediate interactions interaction with the environment, such as cell-cell signaling and nutrient uptake. In the secretory pathway, newly synthesized proteins are co-translational modified by N-glycosylation at Asn-X-Ser/Thr (X≠Pro) sites [NXS/T] sites, and ancient modification that promotes folding and proteostasis in the ER. Glycoproteins transit from the ER to the Golgi in metazoans where the N-glycans are trimmed by glycosidases and modified by branching N-acetylglucosaminyltransferases (MGAT-1,-2,-3,-4, and -5). These enzyme reactions require uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), generated by the hexosamine biosynthesis pathway (HBP) from glucose, glutamine and acetyl-coenzyme A. The GlcNAc-branched N-glycans are elongated by additional enzymes creating β-galactoside binding sites for Galectins, which crosslink and alter the dynamics of glycoproteins at the cell surface (1-5). The Galectin-3 lattice is a planar phase transition that slow loss of receptors and solute transporters to endocytosis and caveolae (6,7). The number of NXS/T sites (sequence encoded), expression of the Golgi enzymes (tissue specific) and UDP-GlcNAc levels (metabolism) regulate the affinity of glycoproteins for Galectin lattice (6,8-10). UDP-GlcNAc synthesis by HBP competes with glycolysis and glutaminolysis for substrates, thus central metabolism is a critical regulator of cytokine receptor residency at the cell surface by the Galectin lattice (11-13).

Computational model of N-glycan branching and opposing signaling pathways.

The Galectin lattice regulates opposing pathways including T cell receptor and CTLA-4 in lymphocytes (1), EGF and TGF-beta receptors in cancer cells (3); and insulin and glucagon receptor in liver (5). Our ODE model stimulates HBP, thereby N-glycan branching and the affinity of receptors for the Galectin-3 lattice. Growth receptors have evolved with higher density of NXS/T sites and are therefore retained at the cell surface by the Galectin lattice at low UDP-GlcNAc, while receptors with four or less NXS/T sites require higher UDP-GlcNAc and branching to be retained by the Galectin lattice. Receptors with low site multiplicity are ultimately recruited at sufficient levels to mediate negative feedback (3). 
The Mgat5 null mice lack the higher affinity tetra-antennary ligands, and display altered signaling in opposing pathways leading to imbalances that reduce fitness and longevity (dotted green line). The Mgat5 null phenotypes include slower cancer progression (14-16) and cell motility and invasion (4,17,18). However, early loss of stem cells, deterioration of muscle and bone and a shortened lifespan (19). Mgat5 null mice are resistance to weight gain on a high fat diet and display hypoglycemia due to a deficiency in surface retention of glucagon receptor in liver (8,19). Mgat5 null mice display hypersensitivity to inducers of inflammation (2,20,21) and EAE, a model of multiple sclerosis (22,23) and final a deficiency in learned behaviours (24). Drs. Michael Demetriou at UC Irvine and Ivan Robert Nabi at UBC have been wonderful collaborators making major contributions to this work over the years. A clinical trial with oral GlcNAc in MS patients increased N-glycan branching on lymphocytes and inhibits inflammation and neurodegeneration markers (25). Dr. Demetriou is also planning clinical trials by immune therapy targeting cancer associated changes in glycosylation.

Genetic code asymmetry supports diversity through experimentation with posttranslational modifications.

The topology of the genetic code clusters synonymous codons, and amino acids with similar chemical properties, which minimizes the deleterious effects of mutations and translation error. The evolutionary intermediates leading to the universal code ultimately minimizing the cost of information flow while maximizing amino acid diversity. However, mapping up to 25 amino acids in the triplet nucleotide format is possible based on information theory. Thus, fixation of the genetic code appears to have compromised on the total number of amino acids to allow for greater asymmetries in codon number per amino acid. Our phylogenetic analysis suggests that this asymmetry increases mutational experimentation with amino acids that are more likely to yield phenotypic diversity. Lys, and Asn are each encoded by two A-rich codons and therefore more likely to undergo nonsynonymous mutation than amino with more codons. Site loss followed by site gain is more likely to occur elsewhere, thus enhanced rate of experimentation with PTM sites (methylation, acetylation, ubiquitination and N-glycosylation). N-glycosylation sites are ~98% at bipartite motif NXS/T(X≠ P) by encoded (i.e., two Asn and ten Ser/Thr codons), a consistency and strong asymmetry that allowed us to measure repositioning of sites and the effect of coding asymmetry. The data is consistent with a clockwise loss-gain cycle that has repositioned sites with increasing positive selection during metazoan evolution (26,27).

Essential amino acid exchangers are regulated by glycosylated adaptors (28).

The import and balance of essential amino acid (EAA) in cells is dependent on nutrient flux to HBP and N-glycan branching on SLC3A2 (4F2hc, CD98), a transmembrane glycoprotein that forms a heterodimer with SLC7A family of essential amino acid exchangers. SLC3A2 bringing N-glycans to the heterodimer, as these exchangers are not N-glycosylated. Selective pressures on SLC3A2 N-glycosylation sites have been greater than other adaptors to ion transporters. Ancestral sites at four of eight positions in rodents varied locally by about 3-6 AAs over mammalian evolution but are absent in primates where a novel site was acquired at N381, and the other three sites at N365, N424 and N506 are conserved. We identify unique N-glycan structural profiles at each of the four sites and show that residue N381 and N365 of SLC3A2 interact with the Galectin-3 lattice and promote SLC3A2*SLC7A5 surface retention, transport activity and clustering with amino acid/Na+ symporters (SLC1A4, SLC1A5), and regulate sorting turnover by GL-Lect. EAA in SLC3A2 KO cells were decreased, while HBP substrates and UDP-GlcNAc increased, suggesting positive feedback directed at rebalancing EAA/Gln/Glu by increasing N-glycan branching (28).

Gene purging and the evolution of Neoave metabolism and longevity (29).

Maintenance of the proteasome requires oxidative phosphorylation (ATP) and mitigation of oxidative damage, in an increasingly dysfunctional relationship with aging. SLC3A2 plays a role on both sides of this dichotomy as an adaptor to SLC7A5, a transporter of branched-chain amino acids (BCAA: Leu, Ile, Val), and to SLC7A11, a cystine importer supplying cysteine to the synthesis of the antioxidant glutathione. Intriguingly, the evolution of modern birds (Neoaves) has entailed the purging of genes (~25% coding sequences) including SLC3A2, SLC7A5, -7, -8, -10, and SLC1A4, -5, largely removing BCAA exchangers and their interacting Na(+)/Gln symporters in pursuit of improved energetics. Notably, export of Gln with the import of EAA by SLC3A2*SLC7A5 requires the recovery of Gln by AA/Na+ symporter at the cost (ATP) of maintaining the Na+/K+ gradient by the ATPase exchangers. Duplications of the bidirectional α-ketoacid transporters SLC16A3, SLC16A7, the cystine transporters SLC7A9, SLC7A11, and N-glycan branching enzymes MGAT4B, MGAT4C in Neoaves suggests a shift to the transport of deaminated essential amino acid, and stronger mitigation of oxidative stress supported by the Galectin lattice. We suggest that Alfred Lotka's theory of natural selection as a maximum power organizer (PNAS 8:151,1922) made an unusually large contribution to Neoave evolution.

Intriguingly, Neoaves have purged CDKN1A (P21) and CDKN2A (P16) as well as two associated kinases CDK2 and CDK4 that play a role in metabolism, cell cycle and senescence.  Further analysis of Neoave genomes may reveal higher-dimensional synthetic gene interactions beyond what can be achieved with inbred strains of mice and dogs. The evolution of birds may be viewed as a gain-of-function, gene drop-out experiment driven by adaptation to a volant lifestyle, which has resulted in a remarkable radiation of species occupying ecosystems worldwide and many with extended longevity. Further molecular analysis of Neoaves and Bats may reveal novel rewiring with applications for human health and longevity (29).

Hexosamine biosynthesis pathway in C. elegans development, stress and aging.

Dr. Wendy Johnston in our lab has shown that C. elegans require a large increase in UDP-GlcNAc very early in development for the synthesis of eggshell chitin, a GlcNAcβ1-4 polymer. Chitin forms a protective barrier that blocks entry by supernumerary sperm during fertilization. Synthesis of chitin depends on glucosamine-6-phosphate N-acetyltransferase 2 (GNA-2), a hexosamine pathway enzyme which is rate limiting for UDP-GlcNAc biosynthesis in the C. elegans early zygote (30-32). Gna-2 null mutants are maternal effect embryonic lethal. Rapid and asymmetric extrusion of eggshell chitin is required for movement of the sperm pronucleus to the cortex, as well as reorganization of the cytoskeleton and anterior-posterior polarization. Chitin is also crucial for high fidelity meiosis, polar body extrusion, and turnover of oocyte proteins during the cellular switch to a zygotic phenotype. 

A screen for gna-2 suppressors yielded mutants of sup-46  encoding an RNA-binding protein (C25A1.4) that localizes to stress granules and increases the gna-1 expression (33). Stress granules occur by phase transition at critical concentrations of interacting RNA and proteins (image below).  HNRNPM and MYEF2 are human homologs of SUP-46 also found in RNA stress granules. SUP-46 regulated a set of transcripts that overlap extensively with those regulated by the small RNA-binding Argonaute proteins, required for gametogenesis, early development and stress mitigation. Importantly, SUP-46 has an essential function in preserving paternally mediated transgenerational germline immortality. 

Dr. Joe Culotti has identified genetic and environmental factors that act through protein glycosylation to navigate gonad distal tip cell (DTC) migration during embryogenesis (34). Working with Joe, we find that  mutation of glycosyltransferases encoding branching in the N-glycosylation pathway, and elongation in the chondroitin pathway display defects in phase 2 (ventral to dorsal) migration of the DTC, with penetrance that is temperature sensitive. N-glycosylation and chondroitin mutations displayed additive penetrance (>90%), suggesting compensation and redundancy of these pathways in phase 2 DTC guidance. Both N-glycans and chondroitin have beta-galactoside sequences with affinity for Galectins (in preparation, 2024).

Dr. Charles Warren, a talented postdoctoral fellow, initiated the C. elegans work in my lab. He was first to clone gly-2, which encoded worm MGAT5 activity and showed gly-2 can rescue an Mgat5 deficiency in mammalian cells (35,36). Working with Aldis Krizus, he also mapped the expression patterns six nonessential C. elegans core 2/I N-acetylglucosaminyltransferase homologues (37,38). Charles became assistant Professor at University of New Hampshire in 2003. He designed a study of congenital disorder of glycosylation in C. elegans; a genome-wide RNAi screen to identify N-glycosylation-dependent loci (39). Tragically, Charles died in a paragliding accident in 2005.

Polo-like kinase-4

Polo-like kinase 4 (Plk4) is a serine/threonine kinase first cloned in our Lab as named SAK, a homolog of polo kinase (PLK) and subsequently named PLK4 (40-42). Plk4 is required for centrosome duplication and fidelity of chromosome segregation at mitosis. Plk4 haploinsufficiency promotes mitotic instability and carcinogenesis (43,44). Work on Plk4 continues, led by Dr. Carol Swallow at LTRI. PLK4 is found at high levels in some aggressive cancers of the colorectum, pancreas and breast (45). Plk4 also regulates cancer cell migration and invasion (44,46,47). Plk4 inhibitors are being developed by Phara, and clinical trials in cancer patients are showing promise.
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REFERENCES

  1. Demetriou, M., Granovsky, M., Quaggin, S., and Dennis, J. W. (2001) Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation. Nature 409, 733-739
  2. Partridge, E. A., Le Roy, C., Di Guglielmo, G. M., Pawling, J., Cheung, P., Granovsky, M., Nabi, I. R., Wrana, J. L., and Dennis, J. W. (2004) Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science 306, 120-124
  3. Lau, K. S., Partridge, E. A., Grigorian, A., Silvescu, C. I., Reinhold, V. N., Demetriou, M., and Dennis, J. W. (2007) Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell 129, 123-134
  4. Lajoie, P., Partridge, E. A., Guay, G., Goetz, J. G., Pawling, J., Lagana, A., Joshi, B., Dennis, J. W., and Nabi, I. R. (2007) Plasma membrane domain organization regulates EGFR signaling in tumor cells. J Cell Biol 179, 341-356
  5. Johswich, A., Longuet, C., Pawling, J., Abdel Rahman, A., Ryczko, M., Drucker, D. J., and Dennis, J. W. (2014) N-glycan remodeling on glucagon receptor is an effector of nutrient sensing by the hexosamine biosynthesis pathway. J Biol Chem 289, 15927-15941
  6. Dennis, J. W. (2015) Many Light Touches Convey the Message. Trends Biochem Sci 40, 673-686
  7. Dennis, J. W., Nabi, I. R., and Demetriou, M. (2009) Metabolism, cell surface organization, and disease. Cell 139, 1229-1241
  8. Ryczko, M. C., Pawling, J., Chen, R., Abdel Rahman, A. M., Yau, K., Copeland, J. K., Zhang, C., Surendra, A., Guttman, D. S., Figeys, D., and Dennis, J. W. (2016) Metabolic Reprogramming by Hexosamine Biosynthetic and Golgi N-Glycan Branching Pathways. Sci Rep 6, 23043
  9. Abdel Rahman, A. M., Ryczko, M., Nakano, M., Pawling, J., Rodrigues, T., Johswich, A., Taniguchi, N., and Dennis, J. W. (2015) Golgi N-glycan branching N-acetylglucosaminyltransferases I, V and VI promote nutrient uptake and metabolism. Glycobiology 25, 225-240
  10. Dennis, J. W., and Brewer, C. F. (2013) Density-dependent lectin-glycan interactions as a paradigm for conditional regulation by posttranslational modifications. Mol Cell Proteomics 12, 913-920
  11. Araujo, L., Khim, P., Mkhikian, H., Mortales, C. L., and Demetriou, M. (2017) Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation. Elife 6
  12. Mkhikian, H., Mortales, C. L., Zhou, R. W., Khachikyan, K., Wu, G., Haslam, S. M., Kavarian, P., Dell, A., and Demetriou, M. (2016) Golgi self-correction generates bioequivalent glycans to preserve cellular homeostasis. Elife 5
  13. Wellen, K. E., Lu, C., Mancuso, A., Lemons, J. M., Ryczko, M., Dennis, J. W., Rabinowitz, J. D., Coller, H. A., and Thompson, C. B. (2010) The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev 24, 2784-2799
  14. Granovsky, M., Fata, J., Pawling, J., Muller, W. J., Khokha, R., and Dennis, J. W. (2000) Suppression of tumor growth and metastasis in Mgat5-deficient mice. Nature Medicine 6, 306-312
  15. Beheshti Zavareh, R., Sukhai, M. A., Hurren, R., Gronda, M., Wang, X., Simpson, C. D., Maclean, N., Zih, F., Ketela, T., Swallow, C. J., Moffat, J., Rose, D. R., Schachter, H., Schimmer, A. D., and Dennis, J. W. (2012) Suppression of cancer progression by MGAT1 shRNA knockdown. PLoS ONE 7, e43721
  16. Cheung, P., and Dennis, J. W. (2007) Mgat5 and Pten interact to regulate cell growth and polarity. Glycobiology 17, 767-773
  17. Boscher, C., Zheng, Y. Z., Lakshminarayan, R., Johannes, L., Dennis, J. W., Foster, L. J., and Nabi, I. R. (2012) Galectin-3 protein regulates mobility of N-cadherin and GM1 ganglioside at cell-cell junctions of mammary carcinoma cells. J Biol Chem 287, 32940-32952
  18. Lajoie, P., Kojic, L. D., Nim, S., Li, L., Dennis, J. W., and Nabi, I. R. (2009) Caveolin-1 regulation of dynamin-dependent, raft-mediated endocytosis of cholera toxin b-subunit occurs independently of caveolae. J Cell Mol Med
  19. Cheung, P., Pawling, J., Partridge, E. A., Sukhu, B., Grynpas, M., and Dennis, J. W. (2007) Metabolic homeostasis and tissue renewal are dependent on beta1,6GlcNAc-branched N-glycans. Glycobiology 17, 828-837
  20. Grigorian, A., Lee, S. U., Tian, W., Chen, I. J., Gao, G., Mendelsohn, R., Dennis, J. W., and Demetriou, M. (2007) Control of T Cell-mediated autoimmunity by metabolite flux to N-glycan biosynthesis. J Biol Chem 282, 20027-20035
  21. Lee, S. U., Grigorian, A., Pawling, J., Chen, I. J., Gao, G., Mozaffar, T., McKerlie, C., and Demetriou, M. (2007) N-glycan processing deficiency promotes spontaneous inflammatory demyelination and neurodegeneration. J Biol Chem 282, 33725-33734
  22. Morgan, R., Gao, G., Pawling, J., Dennis, J. W., Demetriou, M., and Li, B. (2004) N-acetylglucosaminyltransferase V (Mgat5)-mediated N-glycosylation negatively regulates Th1 cytokine production by T cells. J Immunol 173, 7200-7208
  23. Mkhikian, H., Grigorian, A., Li, C. F., Chen, H. L., Newton, B., Zhou, R. W., Beeton, C., Torossian, S., Tatarian, G. G., Lee, S. U., Lau, K., Walker, E., Siminovitch, K. A., Chandy, K. G., Yu, Z., Dennis, J. W., and Demetriou, M. (2011) Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis. Nat Commun 2, 334
  24. Soleimani, L., Roder, J. C., Dennis, J. W., and Lipina, T. (2008) Beta N-acetylglucosaminyltransferase V (Mgat5) deficiency reduces the depression-like phenotype in mice. Genes Brain Behav 7, 334-343
  25. Sy, M., Newton, B. L., Pawling, J., Hayama, K. L., Cordon, A., Yu, Z., Kuhle, J., Dennis, J. W., Brandt, A. U., and Demetriou, M. (2023) N-acetylglucosamine inhibits inflammation and neurodegeneration markers in multiple sclerosis: a mechanistic trial. Journal of neuroinflammation 20, 209
  26. Williams, R., Ma, X., Schott, R. K., Mohammad, N., Ho, C. Y., Li, C. F., Chang, B. S., Demetriou, M., and Dennis, J. W. (2014) Encoding asymmetry of the N-glycosylation motif facilitates glycoprotein evolution. PLoS One 9, e86088
  27. Dennis, J. W. (2017) Genetic code asymmetry supports diversity through experimentation with posttranslational modifications. Curr Opin Chem Biol 41, 1-11
  28. Zhang, C., Shafaq-Zadah, M., Pawling, J., Hesketh, G. G., Dransart, E., Pacholczyk, K., Longo, J., Gingras, A. C., Penn, L. Z., Johannes, L., and Dennis, J. W. (2023) SLC3A2 N-glycosylation and Golgi remodeling regulate SLC7A amino acid exchangers and stress mitigation. J Biol Chem 299, 105416
  29. Ng, D., Pawling, J., and Dennis, J. W. (2023) Gene purging and the evolution of Neoave metabolism and longevity. J Biol Chem 299, 105409
  30. Johnston, W. L., Krizus, A., and Dennis, J. W. (2006) The eggshell is required for meiotic fidelity, polar-body extrusion and polarization of the C. elegans embryo. BMC Biol 4, 35
  31. Johnston, W. L., Krizus, A., and Dennis, J. W. (2010) Eggshell chitin and chitin-interacting proteins prevent polyspermy in C. elegans. Curr Biol 20, 1932-1937
  32. Johnston, W. L., and Dennis, J. W. (2012) The eggshell in the C. elegans oocyte-to-embryo transition. Genesis 50, 333-349
  33. Johnston, W. L., Krizus, A., Ramani, A. K., Dunham, W., Youn, J. Y., Fraser, A. G., Gingras, A. C., and Dennis, J. W. (2017) C. elegans SUP-46, an HNRNPM family RNA-binding protein that prevents paternally-mediated epigenetic sterility. BMC Biol 15, 61
  34. Veyhl, J., Dunn, R. J., Johnston, W. L., Bennett, A., Zhang, L. W., Dennis, J. W., Schachter, H., and Culotti, J. G. (2017) The directed migration of gonadal distal tip cells in Caenorhabditis elegans requires NGAT-1, a ss1,4-N-acetylgalactosaminyltransferase enzyme. PLoS One 12, e0183049
  35. Warren, C. E., Krizus, A., Roy, P. J., Culotti, J. G., and Dennis, J. W. (2002) The Caenorhabditis elegans gene, gly-2, can rescue the N-acetylglucosaminyltransferaseV mutation of Lec4 cells. Journal of Biological Chemistry 277, 22829-22838
  36. Warren, C. E., Krizus, A., Partridge, E. A., and Dennis, J. W. (2002) Caenorhabditis elegans gly-1, a core 2/I N-acetylglucosaminyltransferase homologue, is a glucosyltransferase. Glycobiology 12
  37. Warren, C. E., Krizus, A., and Dennis, J. W. (2001) Complementary expression patterns of six nonessential Caenorhabditis elegans core 2/I N-acetylglucosaminyltransferase homologues. Glycobiology 11, 979-988
  38. Warren, C. E., Krizus, A., Partridge, E. A., and Dennis, J. W. (2001) Caenorhabditis elegans gly-1, a core 2/I N-acetylglucosaminyltransferase homologue, is a glycosyltransferase. Glycobiology 11, 979-988
  39. Struwe, W. B., Hughes, B. L., Osborn, D. W., Boudreau, E. D., Shaw, K. M., and Warren, C. E. (2009) Modeling a congenital disorder of glycosylation type I in C. elegans: a genome-wide RNAi screen for N-glycosylation-dependent loci. Glycobiology 19, 1554-1562
  40. Fode, C., Motro, B., Yousefi, S., Heffernan, M., and Dennis, J. W. (1994) Sak, a murine protein-serine/threonine kinase that is related to the Drosophila polo kinase and involved in cell proliferation. Proc Natl Acad Sci USA 91, 6388-6392
  41. Fode, C., Binkert, C., and Dennis, J. W. (1996) Constitutive expression of murine Sak-a suppresses cell growth and induces multinucleation. Molecular and Cellular Biology 16, 4665-4672
  42. Hudson, J. W., Chen, L., Fode, C., Binkert, C., and Dennis, J. W. (2000) Sak kinase gene structure and transcriptional regulation. Gene 241, 65-73
  43. Ko, M. A., Rosario, C. O., Hudson, J. W., Kulkarni, S., Pollett, A., Dennis, J. W., and Swallow, C. J. (2005) Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis. Nat Genet 37, 883-888
  44. Rosario, C. O., Ko, M. A., Haffani, Y. Z., Gladdy, R. A., Paderova, J., Pollett, A., Squire, J. A., Dennis, J. W., and Swallow, C. J. (2010) Plk4 is required for cytokinesis and maintenance of chromosomal stability. Proc Natl Acad Sci USA 107, 6888-6893
  45. Macmillan, J. C., Hudson, J. W., Bull, S., Dennis, J. W., and Swallow, C. J. (2001) Comparative expression of the mitotic regulators SAK and PLK in colorectal cancer. Ann Surg Oncol 8, 729-740
  46. Rosario, C. O., Kazazian, K., Zih, F. S., Brashavitskaya, O., Haffani, Y., Xu, R. S., George, A., Dennis, J. W., and Swallow, C. J. (2015) A novel role for Plk4 in regulating cell spreading and motility. Oncogene 34, 3441-3451
  47. Kazazian, K., Go, C., Wu, H., Brashavitskaya, O., Xu, R., Dennis, J. W., Gingras, A. C., and Swallow, C. J. (2017) Plk4 Promotes Cancer Invasion and Metastasis through Arp2/3 Complex Regulation of the Actin Cytoskeleton. Cancer Res 77, 434-447

 

 

 

 

 

          
 

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