Receptors Respond to Metabolic Flux

Science's STKE  10 Apr 2007:
Vol. 2007, Issue 381, pp. tw122
DOI: 10.1126/stke.3812007tw122

Many cell surface proteins, including receptors, are N-glycosylated as they transit through the biosynthetic pathway. Proteins containing branched structures with poly-N-acetyllactosamine show a higher affinity for galectins, cell-surface proteins that bind glycosylated proteins, than proteins with less branched structures. The galectin interaction appears to limit endocytosis of the receptors. The formation of branched structures requires the intermediate formed by the activity of N-acetylglycosaminyltransferase V (Mgat5), which is dependent on the concentration of UDP-N-acetylglucosamine (UDP-GlcNAc), a product of the hexosamine pathway. Lau et al. combined mathematical modeling of glycosylation branching and the effects of this on the cell-surface expression and signaling of various types of receptors. They found that supplementation of Mgat5–/– cells with GlcNAc increased the interaction of epidermal growth factor receptors (EGFRs) and transforming growth factor-β receptors (TGFβRs) with galectin and increased their abundance at the cell surface. Surprisingly, the EGFR with eight N-glycosylation sites showed a hyberbolic increase in responsiveness (phosphorylation of its downstream effector ERK), whereas TGFβR (with only one or two glycosylation sites) showed a sigmoid or switchlike increase in responsiveness (nuclear translocation of its downstream effector Smad proteins) when the Mgat5–/– cells were supplemented with increasing concentrations of GlcNAc. Based on this observation, the authors were able to create a mathematical model that described the dependency of cell surface protein abundance on glycosylation state and metabolic flux through the hexosamine pathway. Receptors that promote proliferation generally have higher numbers of glycosylation sites than those that promote growth arrest and differentiation, and these proliferation-inducing receptors show a hyperbolic increase in responsiveness to increased flux through the hexosamine pathway. Modeling suggested that the switch-like behavior of the growth-arresting receptors allows them to be ultrasensitive to metabolic state. Stanley discusses the implications and next steps for testing this model.

K. S. Lau, E. A. Partridge, A. Grigorian, C. I. Silvescu, V. N. Reinhold, M. Demetriou, J. W. Dennis, Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell 129, 123-134 (2007). [Online Journal]

P. Stanley, A method to the madness of N-glycan complexity? Cell 129, 27-29 (2007). [Online Journal]