Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2012 PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis Schultze, S M ; Hemmings, B A ; Niessen, M ; Tschopp, O Abstract: New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide-3-kinase (PI3K)/v-akt murine thy- moma viral oncogene homologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesity and diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the excep- tion of metformin, which is considered to function mainly by activating AMPK, no treatment for the metabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapies based on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatment of diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signal transduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, and we also discuss current clinical implications. DOI: https://doi.org/10.1017/S1462399411002109 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-56698 Journal Article Published Version Originally published at: Schultze, S M; Hemmings, B A; Niessen, M; Tschopp, O (2012). PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis. Expert Reviews in Molecular Medicine, 14:e1. DOI: https://doi.org/10.1017/S1462399411002109 expert reviews http://www.expertreviews.org/ in molecular medicine PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis Simon M. Schultze1,2, Brian A. Hemmings2, Markus Niessen1 and Oliver Tschopp1,* New therapeutic approaches to counter the increasing prevalence of obesity glucose homeostasis and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesity and diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the exception of metformin, which is considered to function mainly by activating AMPK, no treatment for the metabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapies based on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatment of diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signal transduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, and we also discuss current clinical implications. Metabolic syndrome is generally defined as a coronary heart disease, stroke and nonalcoholic cluster of risk factors for cardiovascular disease fatty liver disease (Refs 3, 4, 5). and type 2 diabetes mellitus (T2DM) including Strict control of the level of circulating glucose central obesity, arterial hypertension, within a narrow physiological range supplies dyslipidaemia and elevated fasting glucose sufficient energy for organs and avoids (Ref. 1). Impaired glucose homeostasis, as hyperglycaemia. Glucose homeostasis is largely observed in patients with metabolic syndrome, maintained by the insulin–glucagon system, PI3K/AKT, MAPK and AMPK signalling: protein kinases in frequently progresses to overt T2DM, which in which compensates for physiological 2010 affected 344 million patients worldwide fluctuations in blood glucose caused by food (Ref. 2). Hyperglycaemia in diabetic patients can intake and physical activity, or by stress lead to life-threatening complications such as conditions such as hypoxia and inflammation. 1Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland 2Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland *Corresponding author: Oliver Tschopp, Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. E-mail: oliver.tschopp@ usz.ch 1 Accession information: doi:10.1017/S1462399411002109; Vol. 14; e1; January 2012 © Cambridge University Press 2012 expert reviews http://www.expertreviews.org/ in molecular medicine Insulin and glucagon are released from β- and α- for proper metabolic control and their cells, respectively, in the endocrine part of the dysfunction often leads to impaired glucose pancreas. Insulin lowers blood glucose by homeostasis, these pathways are attractive stimulating glucose uptake and storage therapeutic targets (Refs 8, 9, 10). However, (glycogen synthesis and lipogenesis) in skeletal PI3K/AKT, MAPK and AMPK are also involved muscle and adipose tissue. In the liver, insulin in several other fundamental cellular processes, blocks the release and neogenesis of glucose and including cell proliferation and survival, and stimulates glucose storage. In addition, insulin thus global therapeutic modification of their stimulates protein synthesis, regulates activities could induce severe side effects. mitochondrial biogenesis and blocks autophagy. Today, specific kinase inhibitors are used Glucagon antagonises the action of insulin, successfully for immunosuppression and in the mostly in the liver, where it stimulates treatment of inflammatory disease and diverse gluconeogenesis and thereby increases blood cancer types. However, because proper glucose level. The secretion of insulin and activation of the PI3K/AKT pathway is required glucagon is regulated in a reciprocal manner, for insulin action, kinase inhibitors targeting glucose homeostasis which avoids glycaemic volatility because of PI3K/AKT and downstream effectors might their opposing effects. It was proposed that the impair metabolic control. Even though glucose-induced secretion of insulin inhibits inappropriate activation of MAPKs, especially of glucagon secretion from α-cells in a paracrine c-Jun N-terminal kinase (MAPK8, JNK), is manner (Ref. 6). Furthermore, incretin hormones considered to have a critical role in acquired [e.g. glucagon-like peptide 1 (GLP-1)] secreted insulin resistance, no therapies based on MAPKs postprandially by the gut potentiate glucose- are available so far. The only drug targeting mediated insulin secretion and block glucagon protein kinase activity that is widely used today secretion (Ref. 7). In addition, physiological in the treatment of insulin resistance and conditions such as low intracellular energy level diabetes is metformin, which is thought to and cellular stress affect whole-body glucose operate mainly by activating AMPK. Although homeostasis by interfering with insulin action. our understanding of the role of protein kinases Signal transduction from a stimulus to the in the regulation of glucose homeostasis has regulation of cellular processes, including those increased significantly during the past decade, involved in glucose homeostasis, is primarily only limited translation into therapies against dependent on protein kinase signalling. On the metabolic syndrome has occurred. The activation, protein kinases determine the output purpose of this present review is to summarise of metabolic processes by transcriptional and the signal transduction mechanisms involving post-translational regulation of rate-limiting PI3K/AKT, MAPK and AMPK with respect to enzymes, such as glycogen synthase 1 their role in glucose homeostasis and to discuss (GYS1) and fatty acid synthase (FASN, FAS). current clinical implications. The insulin receptor (INSR, IR) activates various downstream pathways that control The PI3K–AKT signalling pathway is the energy homeostasis, including major effector of metabolic insulin action phosphoinositide-3-kinase (PI3K)/v-akt murine Insulin is an indispensable regulator of glucose PI3K/AKT, MAPK and AMPK signalling: protein kinases in thymoma viral oncogene homologue [AKT, also homeostasis, and T2DM is characterised by known as protein kinase B (PKB)] and the postreceptor insulin resistance combined with β- mitogen-activated protein kinase 3/1 (MAPK3/ cell failure. Insulin signalling is initiated by the 1, ERK1/2). Whereas the PI3K/AKT pathway is binding of insulin to the extracellular α-subunits considered to be the major effector of metabolic of the heterotetrameric IR. This interaction insulin action, insulin-independent kinases also induces conformational changes and facilitates contribute to metabolic control. AMP-activated autophosphorylation of tyrosine residues on protein kinase (AMPK) is mostly activated by the intracellular part of membrane-spanning low intracellular energy levels and inhibits β-subunits. These phosphotyrosines then attract anabolic processes, stimulates energy-producing a family of adaptor molecules, the insulin catabolic processes and lowers blood glucose receptor substrates (IRSs). On interaction with level. Because correct functioning of the PI3K/ the IR, IRS proteins themselves are tyrosine AKT, MAPK and AMPK pathways is essential phosphorylated, which is partially mediated by 2 Accession information: doi:10.1017/S1462399411002109; Vol. 14; e1; January 2012 © Cambridge University Press 2012 expert reviews http://www.expertreviews.org/