Abstract
The phosphatidylinositide 3 kinases (PI3Ks) and their downstream mediators AKT and mammalian target of rapamycin (mTOR) are central regulators of glycolysis, cancer metabolism, and cancer cell proliferation. At the molecular level, PI3K signaling involves the generation of the second messenger lipids phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] and phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2]. There is increasing evidence that PI(3,4)P2 is not only the waste product for the removal of PI(3,4,5)P3 but can also act as a signaling molecule. The selective cellular functions for PI(3,4)P2 independent of PI(3,4,5)P3 have been recently described, including clathrin-mediated endocytosis and mTOR regulation. However, the specific spatiotemporal dynamics and signaling role of PI3K minor lipid messenger PI(3,4)P2 are not well-understood. This review aims at highlighting the biological functions of this lipid downstream of phosphoinositide kinases and phosphatases and its implication in cancer metabolism.
Highlights
Phosphoinositides are synthetized in the endoplasmic reticulum by phosphatidylinositol synthase (PIS) and consist of a glycerol backbone, an inositol ring, and two fatty acid chains; in humans, these are usually enriched with stearic acid and arachidonic acid at the sn-1 and sn2 position of their glycerol backbone, respectively [1, 2]
INPP5E has a broad pattern of expression and it was reported to negatively regulate insulin-like growth factor 1-mediated AKT phosphorylation, counteracting the phosphatidylinositide 3 kinases (PI3Ks) axis
phosphatase tensin homolog (PTEN) loss leads to PI3K/AKT-mediated mammalian target of rapamycin (mTOR) activation, regulating cell metabolism and promoting glycolysis and pentose phosphate pathway (PPP) [36, 37]
Summary
The phosphatidylinositide 3 kinases (PI3Ks) and their downstream mediators AKT and mammalian target of rapamycin (mTOR) are central regulators of glycolysis, cancer metabolism, and cancer cell proliferation. PI3K signaling involves the generation of the second messenger lipids phosphatidylinositol 3,4,5-trisphosphate [PI[3,4,5]P3] and phosphatidylinositol 3,4-bisphosphate [PI[3,4]P2]. The selective cellular functions for PI[3,4]P2 independent of PI[3,4,5]P3 have been recently described, including clathrin-mediated endocytosis and mTOR regulation. The specific spatiotemporal dynamics and signaling role of PI3K minor lipid messenger PI[3,4]P2 are not well-understood. This review aims at highlighting the biological functions of this lipid downstream of phosphoinositide kinases and phosphatases and its implication in cancer metabolism
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