Abstract
Class I phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases activated by cell membrane receptors, either receptor tyrosine kinases (RTKs) or G protein–coupled receptors (GPCRs), to catalyze the production of the lipid second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3). These enzymes engage multiple downstream intracellular signaling pathways controlling cell proliferation, survival and migration. In the cardiovascular system, the four class I PI3K isoforms, PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ are differentially expressed in distinct cell subsets which include cardiomyocytes, fibroblasts, endothelial, and vascular smooth muscle cells as well as leukocytes, suggesting specific functions for distinct PI3K isoenzymes. During the last decades, genetic disruption studies targeting different PI3K genes have elucidated the contribution of specific isoenzymes to cardiac and vascular function regulation, highlighting both beneficial and maladaptive roles. New layers of complexity in the function of PI3Ks have recently emerged, indicating that distinct PI3K isoforms are interconnected by various crosstalk events and can function not only as kinases, but also as scaffold proteins coordinating key signalosomes in cardiovascular health and disease. In this review, we will summarize major breakthroughs in the comprehension of detrimental and beneficial actions of PI3K signaling in cardiovascular homeostasis, and we will discuss recently unraveled cross-talk and scaffold mechanisms as well as the role of the less characterized class II and III PI3K isoforms.
Highlights
Phosphoinositide 3-kinases (PI3Ks) are a family of lipid and protein kinases that primarily function by catalyzing the phosphorylation of D3 position on the inositol ring of phosphatidylinositols (PtdIns)
PI3Kγ lipid kinase activity is negligible in physiological conditions, owing to both low expression levels and protein kinase A (PKA)-dependent phosphorylation, but results dramatically upregulated under adrenergic stress, such as that occurring in congestive heart failure (Perino et al, 2011)
Our understanding of Vps34 kinase activity is still incomplete and further studies are required to clarify this issue. These studies underscore both adaptive and maladaptive actions of PI3K signaling in cardiovascular homeostasis, with class I PI3Kα having prominent beneficial effects, including enhanced physiological hypertrophy and contractility, and PI3Kγ mediating detrimental signals leading to β-adrenergic receptor (β-AR) cascade inhibition
Summary
Phosphoinositide 3-kinases (PI3Ks) are a family of lipid and protein kinases that primarily function by catalyzing the phosphorylation of D3 position on the inositol ring of phosphatidylinositols (PtdIns). Different PI3K isoforms show peculiar expression patterns, with PI3Kα being ubiquitously expressed and enriched in cardiomyocytes, and PI3Kγ functioning in both leukocytes and cardiac cells.
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