Abstract
N-Glycan branching in the medial-Golgi generates ligands for lattice-forming lectins (e.g., galectins) that regulate surface levels of glycoproteins including epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) receptors. Moreover, functional classes of glycoproteins differ in N-glycan multiplicities (number of N-glycans/peptide), a genetically encoded feature of glycoproteins that interacts with metabolic flux (UDP-GlcNAc) and N-glycan branching to differentially regulate surface levels. Oncogenesis increases beta1,6-N-acetylglucosaminyltransferase V (encoded by Mgat5) expression, and its high-affinity galectin ligands promote surface retention of growth receptors with a reduced dependence on UDP-GlcNAc. Mgat5(-/-) tumor cells are less metastatic in vivo and less responsive to cytokines in vitro, but undergo secondary changes that support tumor cell proliferation. These include loss of Caveolin-1, a negative regulator of EGF signaling, and increased reactive oxygen species, an inhibitor of phosphotyrosine phosphatases. These studies suggest a systems approach to cancer treatment where the surface distribution of receptors is targeted through metabolism and N-glycan branching to induce growth arrest.
Highlights
Cancer invasion and metastasis is associated with changes in cell growth control and morphology
Expression of epidermal growth factor receptor (EGFR) family members in breast cancer correlates with aggressive tumor behavior and reduced survival time (Slamon et al 1987)
EGFR in endosomes can activate growth signaling with minimal occupancy by ligand (Reynolds et al 2003; Offterdinger et al 2004), and it has been suggested that growth signaling is largely constitutive were it not for extracelluar cues and receptors that suppress growth (Harris 2004)
Summary
Cancer invasion and metastasis is associated with changes in cell growth control and morphology. Damage-induced S- and M-phase checkpoints are deficient in PyMT Mgat5−/− tumor cells, while rates of replication and death are increased (Mendelsohn et al 2007) These results suggest that Mgat expression in tumor cells regulates cell-cycle progression, presumably by sensitizing cells to extracellular cues for arrest signaling. GlcNAc titration into cultured cells increases UDPGlcNAc concentrations with Michaelis–Menten kinetics, but the tri- and tetraantennary N-glycans increase with sigmoidal kinetics (Figure 3A) These dynamics are due to biochemical features of the pathway, notably decreasing enzyme activities moving down the branching pathway, decreasing affinities for a common substrate (UDP-GlcNAc), a strict sequential order of reactions, and limited reaction times due to transit of glycoprotein substrates through the Golgi (Lau et al 2007). Consistent with the experimental data, low-multiplicity glycoproteins increase with a sigmoidal response to UDP-GlcNAc, mirroring the ultrasensitive output of tri- and tetraantennary Nglycans (Figure 3C)
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