Role of Class II Phosphoinositide 3-Kinase PI3K-C2α in pancreatic β cell function

Abstract

Phosphoinositide 3-kinases (PI3Ks) are a family of enzymes that catalyse the synthesis of different lipid second messengers, regulating a plethora of intracellular functions. Deregulation of their signalling pathway has different functional consequences, and it has been associated with a variety of human diseases. The existence of eight distinct isoforms, divided into three classes, has raised in the past many questions on whether and to which extent their role was redundant or overlapping. The study of their intracellular signalling pathways and cellular functions is crucial, because some of these isoforms have been identified as important therapeutic targets. The most investigated PI3Ks belong to the class I subfamily, and they have a well established role in the regulation of cell growth, survival and proliferation. In the past years, attention and research efforts focussed on class I isoforms and alteration of their signalling pathways, one of the most common causes of cancer. More recently, evidence indicated that the least investigated class II PI3Ks have different intracellular roles. This work focussed on the class II isoform PI3K-C2α, the study of its intracellular function(s) in pancreatic β cells and the implications of its inhibition through downregulation in pancreatic β cells homeostasis. It was reported that PI3K-C2α has a crucial role insulin granules exocytosis. This study has demonstrated that this enzyme synthesises the lipid product PtdIns3P specifically at the plasma membrane of pancreatic β cells upon depolarisation of the plasma membrane and stimulation of insulin secretion. Moreover, the data herein presented indicated for the first time that glucose-induced activation of PI3K-C2α is able to protect β cells from cell death induced by nutrients deprivation. Analysis of the intracellular pathways stimulated by glucose indicated that PI3K-C2α is able to modulate the activity of mTOR and its downstream effectors, key regulators of cell proliferation and growth. Importantly, the activation of mTOR pathway upon glucose does not seem to involve the activation of the upstream regulator Akt or class I PI3K, suggesting a novel intracellular pathway stimulated by glucose.