title: Inhibition of insulin signaling in endothelial cells by protein kinase C-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase (PI3K).
abstract: The regulation of endothelial function by insulin is consistently abnormal in insulin-resistant states and diabetes. Protein kinase C (PKC) activation has been reported to inhibit insulin signaling selectively in endothelial cells via the insulin receptor substrate/PI3K/Akt pathway to reduce the activation of endothelial nitric-oxide synthase (eNOS). In this study, it was observed that PKC activation differentially inhibited insulin receptor substrate 1/2 (IRS1/2) signaling of insulin's activation of PI3K/eNOS by decreasing only tyrosine phosphorylation of IRS2. In addition, PKC activation, by general activator and specifically by angiotensin II, increased the phosphorylation of p85/PI3K, which decreases its association with IRS1 and activation. Thr-86 of p85/PI3K was identified to be phosphorylated by PKC activation and confirmed to affect IRS1-mediated activation of Akt/eNOS by insulin and VEGF using a deletion mutant of the Thr-86 region of p85/PI3K. Thus, PKC and angiotensin-induced phosphorylation of Thr-86 of p85/PI3K may partially inhibit the activation of PI3K/eNOS by multiple cytokines and contribute to endothelial dysfunction in metabolic disorders.
authors.affiliation: Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maeno
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Kyoungmin
authors.initials: K
authors.lastname: Park
authors.forename: Christian
authors.initials: C
authors.lastname: Rask-Madsen
authors.forename: Benbo
authors.initials: B
authors.lastname: Gao
authors.forename: Motonobu
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Liu
authors.forename: I-Hsien
authors.initials: IH
authors.lastname: Wu
authors.forename: Morris F
authors.initials: MF
authors.lastname: White
authors.forename: Edward P
authors.initials: EP
authors.lastname: Feener
authors.forename: George L
authors.initials: GL
authors.lastname: King
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008659:Metabolic Diseases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C