The role of PAS kinase in regulating energy metabolism

Abstract

Metabolic disorders, such as diabetes and obesity, are fundamentally caused by cellular energy imbalance and dysregulation. Therefore, understanding the regulation of cellular fuel and energy metabolism is of great importance to develop effective therapies for metabolic disease. The cellular nutrient and energy sensors, AMPK and TOR, play a key role in maintaining cellular energy homeostasis. Like AMPK and TOR, PAS kinase (PASK) is also a nutrient responsive protein kinase. In yeast, PAS kinase phosphorylates the enzyme Ugp1 and thereby shifts glucose partitioning toward cell wall glucan synthesis at the expense of glycogen synthesis. Consistent with this function, yeast PAS kinase is activated by both cell integrity stress and growth in non-fermentative carbon sources. PASK is also important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular level. In cultured pancreatic beta-cells, PASK is activated by elevated glucose concentrations and is required for glucose-stimulated transcription of the insulin gene. PASK knockdown in cultured myoblasts causes increased glucose oxidation and elevated cellular ATP levels. Mice lacking PASK exhibit increased metabolic rate and resistance to diet-induced obesity. Interestingly, PGC-1 expression and AMPK and TOR activity were not affected in PASK deficient mice, suggesting PASK may exert its metabolic effects through a new mechanism. We propose that PASK plays a significant role in nutrient sensing, metabolic regulation, and energy homeostasis, and is a potential therapeutic target for metabolic disease.

Per-Arnt-Sim Kinase Regulates Pancreatic Duodenal Homeobox-1 Protein Stability via Phosphorylation of Glycogen Synthase Kinase 3β in Pancreatic β-Cells

“…PASK is an evolutionary conserved, nutrient-responsive serine/threonine kinase (17,21,32). In Saccharomyces cerevisiae, the PASK orthologs Psk1 and Psk2 regulate the partitioning of glucose between storage as glycogen or utilization (33).…”

Efficient gene targeting in Drosophila by direct embryo injection with zinc-finger nucleases

“…Two of the pask mutations are frameshifts that should be nulls; their phenotype is currently under examination. Loss of PAS kinase has shown rather subtle effects in other organisms (31), and the ease of manipulating its expression in Drosophila should aid in characterizing the enzyme's functions.…”

“…To demonstrate the utility of the injection method, we designed new pairs of ZFNs for targets in the Drosophila genes for coilin, a defining component of nuclear Cajal bodies (29,30), and PAS kinase, a serine/threonine kinase that plays a role in metabolic regulation in yeast and mammals (31). The new mutations we generated will allow us to take advantage of Drosophila genetic analysis to study the detailed functions of these proteins.…”

PAS Kinase Is a Nutrient and Energy Sensor in Hypothalamic Areas Required for the Normal Function of AMPK and mTOR/S6K1

“…In mammals, PASK is involved in the regulation of glucose and energy metabolism homeostasis [1][2][3]. Thus, it has been proposed that PASK is activated by small metabolites and may regulate glycogen synthesis and protein translation.…”