PI(3,4)P2 Signaling in Cancer and Metabolism

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.

Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites

“…Given the pivotal roles of inositol lipids in the regulation of membrane traffic 1,39 we screened an siRNA smart pool library encoding all known human inositol kinases and phosphatases for a possible function in the internalization of Shiga toxin, a bacterial toxin known to enter cells via a glycosphingolipid-mediated clathrin-independent endocytosis (CIE) pathway. Consistent with the established function of phosphatidylinositol-bisphosphates in endocytosis 1,27,40 , we found CIE of Shiga toxin to be strongly reduced upon cellular depletion of phosphatidylinositol (PI) 4phosphate 5-kinase type IB (PIPKIB) or PI 3-kinase C2γ (PI3KC2G), i.e., enzymes that synthesize plasma membrane PI (4,5)P 2 or phosphatidylinositol (3,4)-bisphosphate [PI(3,4) P 2 ] 40,41 , respectively (Fig. 1a).…”

Phosphatidylinositol-4,5-Biphosphate (PI(4,5)P2) Is Required for Rapid Endocytosis in Chromaffin Cells

“…Evidence for such scenario has been already shown in pancreatic β cells where PI(4,5)P 2 was found to promote DCVs kiss-and-run mode of insulin secretion [ 29 ]. Nevertheless, phosphatidylinositol-3,4-bisphosphate (PI(3,4)P 2 ) is another important signaling lipid that is mechanistically involved in both clathrin-dependent endocytosis [ 6 , 8 , 30 , 31 ] and clathrin-independent fast endophilin-mediated endocytosis (FEME) [ 31 ]. Indirect conversion of PI(4,5)P 2 to PI(3,4)P 2 is required during the late stage of the endocytic process in order to recruit PI(3,4)P 2 effectors at endocytic sites and trigger vesicle scission and recycling by dynamin [ 6 , 8 , 30 ].…”

“Modulating Phosphoinositide Profiles as a Roadmap for Treatment in Acute Myeloid Leukemia”

“…In contrast PtdIns(4)P is predominantly found in the Golgi complex ( 9 ), where it modulates Golgi structure and function, whilst PtdIns(3)P and PtdIns(3,5)P 2 are found predominantly within early and late endosomes or lysosomes ( 10 ) ( Figure 1 ). PtdIns(3,4)P 2 is another key molecule, when localized at the plasma membrane it can assist cytoskeletal rearrangements important for clathrin mediated endocytosis, macropinocytosis and lysosomal catabolism, cell migration and, in cancer cells, invasion ( 11 ). Moreover PtdIns(3,4)P 2 can mediate glucose uptake and insulin signalling and become a key second messenger ( 11 ).…”