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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.
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http://dx.doi.org/10.3390/biom9030104 | DOI Listing |
Biochim Biophys Acta Mol Cell Biol Lipids
September 2025
Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, V8W 2Y2, Canada; University of Victoria Genome BC Proteomics Centre, Vi
The class I phosphoinositide 3-kinase pathway (PI3K) is a master regulator of cellular growth, and plays essential roles in controlling immune cell function, metabolism, chemotaxis and proliferation. Activation of class I PI3Ks generates the signalling lipid PIP that activates multiple pro-growth signalling pathways. Class I PI3Ks can be activated by multiple plasma membrane stimuli, including G-protein coupled receptors, Ras superfamily GTPases, and receptor tyrosine kinases.
View Article and Find Full Text PDFMol Divers
August 2025
School of Pharmaceutical Science, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China.
Vacuolar sorting protein 34 (VPS34), a sole member of class III phosphoinositide 3-kinase (PI3K), regulates critical cellular processes, such as endosomal trafficking and autophagosome biogenesis, making it a promising target for diseases such as cancer and neurodegenerative disorders. However, developing highly selective inhibitors for VPS34 is challenging due to the structural conservation of its ATP-binding site across PI3Ks. In this study, to elucidate the structural dynamics of selective ligand recognition, we performed molecular dynamics (MD) simulations to explore the conformational landscape of VPS34 in both its apo state and in complex with selective/nonselective ligands.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
August 2025
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
The nonstructural protein 1 (NS1) of influenza A virus performs a broad variety of proviral activities in the infected cell, primarily mediating evasion from the host innate immune response by being the main viral interferon antagonist. However, there are several interactions whose biological relevance remains obscure, such as the ability of NS1 to bind and activate class IA phosphoinositide 3-kinases (PI3Ks). PI3Ks are highly regulated lipid kinases that act as critical nodes in multiple cell signaling networks and are also important proto-oncogenes.
View Article and Find Full Text PDFDis Model Mech
September 2025
Bateson Centre, School of Medicine and Population Health, University of Sheffield, Sheffield S10 2TN, UK.
Class I PI3 kinases (PI3Ks) coordinate the delivery of microbicidal effectors to the phagosome by forming phosphatidylinositol (3,4,5)-trisphosphate (PIP3). However, the dynamics of PIP3 in neutrophils during a live bacterial tissue infection are unknown. We therefore developed an in vivo, live zebrafish infection model that enables visualisation of dynamic changes in Class 1 PI3K signalling in neutrophil phagosomes in real time.
View Article and Find Full Text PDFbioRxiv
May 2025
Department of Molecular Biology, College of Agriculture Life Sciences, and Natural Resources, University of Wyoming, Laramie, Wyoming, United States of America.
Membrane trafficking, including endocytosis and exocytosis, is a complex process that is coordinated by trafficking-associated proteins, cargo molecules, the cytoskeleton, and membrane lipid composition. The NIMA-related kinases NEKL-2 (human NEK8/9) and NEKL-3 (human NEK6/7) are conserved regulators of membrane trafficking in and are required for successful molting. Through a genetic approach, we isolated reduction-of-function mutations in that suppress -associated molting defects.
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