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. 2019 Mar 15;9(3):104.
doi: 10.3390/biom9030104.

Class II PI3Ks at the Intersection Between Signal Transduction and Membrane Trafficking

Free PMC article

Class II PI3Ks at the Intersection Between Signal Transduction and Membrane Trafficking

Jean Piero Margaria et al. Biomolecules. .
Free PMC article


Phosphorylation of inositol phospholipids by the family of phosphoinositide 3-kinases (PI3Ks) is crucial in controlling membrane lipid composition and regulating a wide range of intracellular processes, which include signal transduction and vesicular trafficking. In spite of the extensive knowledge on class I PI3Ks, recent advances in the study of the three class II PI3Ks (PIK3C2A, PIK3C2B and PIK3C2G) reveal their distinct and non-overlapping cellular roles and localizations. By finely tuning membrane lipid composition in time and space among different cellular compartments, this class of enzymes controls many cellular processes, such as proliferation, survival and migration. This review focuses on the recent developments regarding the coordination of membrane trafficking and intracellular signaling of class II PI3Ks through the confined phosphorylation of inositol phospholipids.

Keywords: PI3K-C2α; PI3K-C2β; PI3K-C2γ; PI3K68D; PIK3C2A; PIK3C2B; PIK3C2G; membrane trafficking; piki-1; signal transduction.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Graphical representation of class II phosphoinositide 3-kinases (PI3Ks) in mammals (PIK3C2A, PIK3C2B and PIK3C2G) and their domains: Clathrin binding domain (CBD), Ras binding domain (RBD), TACC3 binding domain (TBD), C2 membrane interacting domain (C2), Helical domain (Helical), Kinase domain (Kinase) and Phox homology domain (PX). The right panel displays known functions of each isoform. The right panel highlight principal cell signaling (black squares) and membrane trafficking (white squares) roles of the three isoforms.
Figure 2
Figure 2
PIK3C2A, PIK3C2B and PIK3C2G in vesicular trafficking and intracellular signaling. PIK3C2A produces localized pools of PI(3,4)P2 on plasma membrane contributing to clathrin-mediated endocytosis (CME) and insulin receptor substrate 1 (IRS1) mediated class I PI3K-dependent phospo-Akt1 (pAkt1) signaling. PIK3C2A generates a pool of PI(3)P on early endosomes (EE) promoting recycling processes toward the recycling compartment (RC) and primary cilium. PIK3C2A and PIK3C2B both participate to clathrin dependent pinocytosis (CDP) on plasma membrane. PIK3C2B produces PI(3,4)P2 on late endosomes/lysosomes (LE/LY) to repress mTORC1 signaling through Raptor. PIK3C2B generates a localized pool of PI(3)P on EE during insulin signaling, on nuclear envelope, and at the leading edge during cell migration. PIK3C2G is recruited on EE by Rab5 to produce PI(3,4)P2 and increases phospho-Akt2 (pAkt2) levels.

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