Ken Lau


Ken Lau

Ex-supervisor: Christopher Hogue, Department of Biochemistry. Current supervisor is James Dennis, Department of Biochemistry.

Ken Lau successfully completed the GBB program in April 2008 - and in fact was the first GBB graduate! He has gone on to a post-doctoral position at Harvard.

A systems biology approach to decoding the function of complex N-glycans

Thesis Abstract

Embryogenesis, tissue repair and adaptive immunity involve developmental sequences of cell proliferation followed by differentiation and cell cycle arrest. Growth factors and other cytokines bind glycoprotein receptors to stimulate growth or arrest signaling, with the net response dependent on the availability of both ligands and receptors. The number of N-glycans (n), a distinct feature of each glycoprotein sequence, cooperates with the physical properties of the Golgi pathway to regulate surface levels of receptors. The Golgi pathway is ultrasensitive to hexosamine flux for the production of tri- and tetraantennary N-glycans, which bind galectins to form a molecular lattice that opposes glycoprotein endocytosis. Glycoproteins with few N-glycans (low n - e.g. TβR, CTLA-4, GLUT4) exhibit enhanced cell surface expression with switch-like responses to increasing hexosamine concentration, whereas glycoproteins with high numbers of N-glycans (high n - e.g. EGFR, IGFR, FGFR, PDGFR) exhibit hyperbolic responses. A bioinformatics survey shows that receptor kinases with high n play roles in metabolism and growth, while those with low n have functions in arrest and differentiation pathways. Computational modeling and experimental data reveal that these features impose a sequence of growth-to-arrest/differentiation, where growth-promoting high n receptors stimulate nutrient flux first, which then drives arrest/differentiation programs by increasing surface levels of low n glycoproteins. Interaction of the N-glycan branching pathway and N-glycan number play important roles in diseases, as evidenced by the identification of synergistic polymorphisms in Mgat1 and CTLA-4 in human multiple sclerosis patients. In order to fully understand the interaction of N-glycan functions with cellular phenotypes, we applied an unbiased screening approach to examine perturbation to N-glycan branching on a global scale. By utilizing microarray analysis and siRNA knockdown, we have identified GIcNAc-sensitive pathways that validate and extend our model, and simultaneously affect growth regulation, complex N-glycan processing, and constitutive endocytosis. Non-intuitive genes of interest identified by our screen include those associated with ionic regulation and proteoglycan biosynthesis. Our results reveal a mechanism for the metabolic regulation of the cellular transition between growth and arrest in mammals that arises from the apparent co-evolution of N-glycan number and branching.

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