title: PAQR3 modulates insulin signaling by shunting phosphoinositide 3-kinase p110α to the Golgi apparatus.
abstract: Phosphoinositide 3-kinase (PI3K) mediates insulin actions by relaying signals from insulin receptors (IRs) to downstream targets. The p110α catalytic subunit of class IA PI3K is the primary insulin-responsive PI3K implicated in insulin signaling. We demonstrate here a new mode of spatial regulation for the p110α subunit of PI3K by PAQR3 that is exclusively localized in the Golgi apparatus. PAQR3 interacts with p110α, and the intracellular targeting of p110α to the Golgi apparatus is reduced by PAQR3 downregulation and increased by PAQR3 overexpression. Insulin-stimulated PI3K activity and phosphoinositide (3,4,5)-triphosphate production are enhanced by Paqr3 deletion and reduced by PAQR3 overexpression in hepatocytes. Deletion of Paqr3 enhances insulin-stimulated phosphorylation of AKT and glycogen synthase kinase 3β, but not phosphorylation of IR and IR substrate-1 (IRS-1), in hepatocytes, mouse liver, and skeletal muscle. Insulin-stimulated GLUT4 translocation to the plasma membrane and glucose uptake are enhanced by Paqr3 ablation. Furthermore, PAQR3 interacts with the domain of p110α involved in its binding with p85, the regulatory subunit of PI3K. Overexpression of PAQR3 dose-dependently reduces the interaction of p85α with p110α. Thus, PAQR3 negatively regulates insulin signaling by shunting cytosolic p110α to the Golgi apparatus while competing with p85 subunit in forming a PI3K complex with p110α.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: Lingdi
authors.initials: L
authors.lastname: Wang
authors.forename: Lu
authors.initials: L
authors.lastname: Zhu
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.forename: Fei
authors.initials: F
authors.lastname: Xiao
authors.forename: Weizhong
authors.initials: W
authors.lastname: Liu
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Feifan
authors.initials: F
authors.lastname: Guo
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Walter G
authors.initials: WG
authors.lastname: Thomas
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006056:Golgi Apparatus / Q000187:drug effects / Q000201:enzymology*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010716:Phosphatidylinositols / Q000096:biosynthesis; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D051275:Glucose Transporter Type 4; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; D008565:Membrane Proteins; D010716:Phosphatidylinositols; C523677:RKTG protein, mouse; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; C118303:phosphoinositide-3,4,5-triphosphate; D058543:Class Ia Phosphatidylinositol 3-Kinase; D011972:Receptor, Insulin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D005947:Glucose