PAS kinase: a nutrient sensing regulator of glucose homeostasis

Abstract

Per-Arnt-Sim (PAS) kinase (PASK, PASKIN, and PSK) is a member of the group of nutrient sensing protein kinases. These protein kinases sense the energy or nutrient status of the cell and regulate cellular metabolism appropriately. PAS kinase responds to glucose availability and regulates glucose homeostasis in yeast, mice, and man. Despite this pivotal role, the molecular mechanisms of PAS kinase regulation and function are largely unknown. This review focuses on what is known about PAS kinase, including its conservation from yeast to man, identified substrates, associated phenotypes and role in metabolic disease.

Keywords: PAS kinase; diabetes; glucose metabolism; nutrient sensing; obesity; signal transduction.

FIG 1

Alignment of the PAS kinase PAS domain and kinase domain amino acid sequences from various model organisms. The amino acid sequence from S. cerevisiae Psk1 (ScPsk1), S. cerevisiae Psk2 (ScPsk2), D. melanogaster (DmPASK), G. gallus (GgPASK), B. taurus (BtPASK), H. sapiens (HsPASK), P. troglodytes (PtPASK), R. norvegicus (RtPASK), D. rerio (DrPASK), and M. musculus (MmPASK) were obtained from GenBank and aligned using the Clustal Omega and Jalview software (49,50). The semiconserved phosphorylation loop threonine is indicated by an asterisk. No discernable PASK homologs were found for the model organisms A. thaliana, O. sativa, C. elegans, or A. mellifera. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

FIG 2

A current model for PAS kinase regulation and function. The PAS domain binds to and inhibits the kinase domain. Under activating growth conditions, such as growth that stimulates respiration or cell integrity stress, a small metabolite (indicated by the star) may bind the PAS domain, releasing it from the kinase domain. Auto or transphosphorylation may also activate PAS kinase or stabilize transient metabolite activation. PAS kinase then phosphorylates downstream targets to regulate glucose metabolism as well as cell proliferation. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]