Cardiac regulation by phosphoinositide 3-kinases and PTEN.
The diverse effects mediated by PI3K/PTEN (phosphoinositide 3-kinase/phosphatase and tensin homologue deleted on chromosome 10) signalling in the heart clearly support an important biological and pathophysiological role for this signalling cascade. PI3Ks are a family of evolutionarily conserved lipid kinases that mediate many cellular responses to physiological and pathophysiological stimuli. Class I PI3K can be activated by either receptor tyrosine kinase/cytokine receptor activation (class IA) or G-protein-coupled receptors (class IB), leading to the generation of phosphatidyl inositol (3,4,5)P3 and recruitment and activation of Akt/protein kinase B, 3'-phosphoinositide-dependent kinase-1 (PDK1), or monomeric G-proteins, and phosphorylation of a wide range of downstream targets including glycogen synthase kinase 3beta (GSK3beta), mTOR (mammalian target of rapamycin), p70S6 kinase, endothelial nitric oxide synthase, and several anti-apoptotic effectors. Class IA (PI3Kalpha, beta, and delta) and class IB (PI3Kgamma) PI3Ks mediate distinct phenotypes in the heart under negative control by the 3'-lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4,5)P3 to generate PtdIns(4,5)P2. PI3Kalpha, PI3Kgamma, and PTEN are expressed in cardiomyocytes, fibroblasts, endothelial cells, and vascular smooth muscle cells, where they modulate cell survival, hypertrophy, contractility, metabolism, and mechanotransduction. The PI3K/PTEN signalling pathways are involved in a wide variety of diseases including myocardial hypertrophy and contractility, heart failure, and preconditioning. In this review, we discuss the signalling pathways mediated by PI3K class I isoforms and PTEN and their roles in cardiac structure and function.
Oudit
Gavin Y
GY
Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada T6G 2B7. gavin.oudit@ualberta.ca
Penninger
Josef M
JM
D000818:Animals; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000503:physiopathology; D006801:Humans; D006984:Hypertrophy / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D019869:Phosphatidylinositol 3-Kinases; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase