The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine

• Published in: Biochimica et biophysica acta Vol. 1800; no. 2; pp. 80 - 95
• Main Authors: Hanover, John A., Krause, Michael W., Love, Dona C.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2010
• Subjects: Acetylglucosamine - physiology; Acetylglucosaminidase - metabolism; AKT; AMPK; Animals; Caenorhabditis elegans; Cancer; Cardiovascular disease; Catalytic Domain; Diabetes; Diabetes Mellitus, Type 2 - physiopathology; Evolution, Molecular; Food; Gene Expression Regulation - physiology; Growth factor; Hexosamine; Humans; Insulin; Insulin Resistance - physiology; MAP Kinase Signaling System - physiology; MAPK; Models, Animal; Models, Molecular; mTOR; N-Acetylglucosaminyltransferases - metabolism; Neurodegeneration; O-GlcNAc; Proteasome Endopeptidase Complex - physiology; Proto-Oncogene Proteins c-akt - physiology; Sirtuins - physiology; Starvation; Neurodegeneration; mTOR; Cardiovascular disease; AMPK; Hexosamine; AKT; Diabetes; MAPK; Insulin; O-GlcNAc; Growth factor; Cancer
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2009.07.017

The enzymes of O-GlcNAc cycling couple the nutrient-dependent synthesis of UDP-GlcNAc to O-GlcNAc modification of Ser/Thr residues of key nuclear and cytoplasmic targets. This series of reactions culminating in O-GlcNAcylation of targets has been termed the hexosamine signaling pathway (HSP). The evolutionarily ancient enzymes of O-GlcNAc cycling have co-evolved with other signaling effecter molecules; they are recruited to their targets by many of the same mechanisms used to organize canonic kinase-dependent signaling pathways. This co-recruitment of the enzymes of O-GlcNAc cycling drives a binary switch impacting pathways of anabolism and growth (nutrient uptake) and catabolic pathways (nutrient sparing and salvage). The hexosamine signaling pathway (HSP) has thus emerged as a versatile cellular regulator modulating numerous cellular signaling cascades influencing growth, metabolism, cellular stress, circadian rhythm, and host–pathogen interactions. In mammals, the nutrient-sensing HSP has been harnessed to regulate such cell-specific functions as neutrophil migration, and activation of B-cells and T-cells. This review summarizes the diverse approaches being used to examine O-GlcNAc cycling. It will emphasize the impact O-GlcNAcylation has upon signaling pathways that may be become deregulated in diseases of the immune system, diabetes mellitus, cancer, cardiovascular disease, and neurodegenerative diseases.