The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine.
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.
Hanover
John A
JA
Laboratory of Cell Biochemistry and Biology, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA. jah@helix.nih.gov
Krause
Michael W
MW
Love
Dona C
DC
D000117:Acetylglucosamine / Q000502:physiology; D000118:Acetylglucosaminidase / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans; D020134:Catalytic Domain; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D019143:Evolution, Molecular; D005502:Food; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D023421:Models, Animal; D008958:Models, Molecular; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D037761:Sirtuins / Q000502:physiology; D013217:Starvation
D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D051057:Proto-Oncogene Proteins c-akt; D000118:Acetylglucosaminidase; D046988:Proteasome Endopeptidase Complex; D037761:Sirtuins; D000117:Acetylglucosamine