The role of phosphoinositide 3-kinase C2alpha in insulin signaling.
The members of the class II phosphoinositide 3-kinase (PI3K) family can be activated by several stimuli, indicating that these enzymes can regulate many intracellular processes. Nevertheless, to date, there has been no definitive identification of their in vivo product, their mechanism(s) of activation, or their precise intracellular roles. By metabolic labeling, we here identify phosphatidylinositol 3-phosphate as the sole in vivo product of the insulin-dependent activation of PI3K-C2alpha, confirming the emerging role of such a phosphoinositide in signaling. We demonstrate that activation of PI3K-C2alpha involves its recruitment to the plasma membrane and that activation is mediated by the GTPase TC10. This is the first report showing a membrane targeting-mediated mechanism of activation for PI3K-C2alpha and that a small GTP-binding protein can activate a class II PI3K isoform. We also demonstrate that PI3K-C2alpha contributes to maximal insulin-induced translocation of the glucose transporter GLUT4 to the plasma membrane and subsequent glucose uptake, definitely assessing the role of this enzyme in insulin signaling.
Falasca
Marco
M
Inositide Signalling Group, Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, Barts and The London, Queen Mary's School of Medicine and Dentistry, University of London, London E1 2AT, United Kingdom. m.falasca@qmul.ac.uk
Hughes
William E
WE
Dominguez
Veronica
V
Sala
Gianluca
G
Fostira
Florentia
F
Fang
Michelle Q
MQ
Cazzolli
Rosanna
R
Shepherd
Peter R
PR
James
David E
DE
Maffucci
Tania
T
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D058541:Class II Phosphatidylinositol 3-Kinases; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000737:chemistry*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D010716:Phosphatidylinositols / Q000737:chemistry*; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction
D051275:Glucose Transporter Type 4; D007328:Insulin; D010716:Phosphatidylinositols; D006160:Guanosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D058541:Class II Phosphatidylinositol 3-Kinases; D005947:Glucose