Hexosamine Signaling Pathway: O-GlcNAc cycling in feast or famine

The Hexosamine signaling pathway terminating in the enzymes of O-GlcNAc cycling lies at the center of many of the major nutrient sensing pathways (p38 MAPK, Insulin-AKT, mTOR, AMPK and SirT1). Broadly speaking these pathways can be considered either ‘Pro-survival’ cascades (shown in green), triggered by stress, DNA damage or starvation or ‘Pro-growth’ cascades (shown in blue) triggered by hormones, cytokines, growth factors, and nutrient excess. The pro-survival cascade limits protein synthesis and triggers nutrient salvage by proteasomal degradation and autophagy. In contrast, the pro-growth cascades enhance protein synthesis and block proteasome activation and autophagy. OGT is recruited to these two cascades by either interacting with PIP3 resulting from PI3K activation (blue double arrow) or by interacting with activated p38 MAPK (green double arrow). These mutually exclusive interactions of OGT produce a binary switch, bringing the nutrient sensing hexosamine signaling module to bear on the two major cascades as indicated in the text. For example, by blunting the action of AKT, OGT limits the pro-growth cascade. OGT also inhibits the proteasome. In contrast, binding to activated p38 MAPK, OGT changes its substrate specificity bringing its nutrient-sensing capabilities to bear on limited stress-specific targets (see text). The net result of these interactions is either nutrient uptake or nutrient salvage and sparing.

Publication

The Hexosamine Signaling Pathway: O-GlcNAc cycling in feast or famine. () John A. Hanover, et al. Biochim Biophys Acta. ;1800(2):80. Figure: F5. All organisms Drosophila melanogaster Homo sapiens

Disease mentions