2014
Kavran, Jennifer M; McCabe, Jacqueline M; Byrne, Patrick O; Connacher, Mary Katherine; Wang, Zhihong; Ramek, Alexander; Sarabipour, Sarvenaz; Shan, Yibing; Shaw, David E; Hristova, Kalina; Cole, Philip A; Leahy, Daniel J
How IGF-1 activates its receptor Journal Article
In: Elife, vol. 3, 2014, ISSN: 2050-084X.
Abstract | Links | BibTeX | Tags: Amino Acid Sequence, Animals, Conserved Sequence, HEK293 Cells, Humans, IGF Type 1, Insulin, Insulin-Like Growth Factor I, Ligands, Mice, Models, Molecular, Molecular Sequence Data, Mutation, Phosphorylation, Protein Binding, Protein Multimerization, Protein Structure, Receptor, Tertiary
@article{1299976,
title = {How IGF-1 activates its receptor},
author = {Jennifer M Kavran and Jacqueline M McCabe and Patrick O Byrne and Mary Katherine Connacher and Zhihong Wang and Alexander Ramek and Sarvenaz Sarabipour and Yibing Shan and David E Shaw and Kalina Hristova and Philip A Cole and Daniel J Leahy},
doi = {10.7554/eLife.03772},
issn = {2050-084X},
year = {2014},
date = {2014-09-01},
journal = {Elife},
volume = {3},
abstract = {The type I insulin-like growth factor receptor (IGF1R) is involved in growth and survival of normal and neoplastic cells. A ligand-dependent conformational change is thought to regulate IGF1R activity, but the nature of this change is unclear. We point out an underappreciated dimer in the crystal structure of the related Insulin Receptor (IR) with Insulin bound that allows direct comparison with unliganded IR and suggests a mechanism by which ligand regulates IR/IGF1R activity. We test this mechanism in a series of biochemical and biophysical assays and find the IGF1R ectodomain maintains an autoinhibited state in which the TMs are held apart. Ligand binding releases this constraint, allowing TM association and unleashing an intrinsic propensity of the intracellular regions to autophosphorylate. Enzymatic studies of full-length and kinase-containing fragments show phosphorylated IGF1R is fully active independent of ligand and the extracellular-TM regions. The key step triggered by ligand binding is thus autophosphorylation.},
keywords = {Amino Acid Sequence, Animals, Conserved Sequence, HEK293 Cells, Humans, IGF Type 1, Insulin, Insulin-Like Growth Factor I, Ligands, Mice, Models, Molecular, Molecular Sequence Data, Mutation, Phosphorylation, Protein Binding, Protein Multimerization, Protein Structure, Receptor, Tertiary},
pubstate = {published},
tppubtype = {article}
}
The type I insulin-like growth factor receptor (IGF1R) is involved in growth and survival of normal and neoplastic cells. A ligand-dependent conformational change is thought to regulate IGF1R activity, but the nature of this change is unclear. We point out an underappreciated dimer in the crystal structure of the related Insulin Receptor (IR) with Insulin bound that allows direct comparison with unliganded IR and suggests a mechanism by which ligand regulates IR/IGF1R activity. We test this mechanism in a series of biochemical and biophysical assays and find the IGF1R ectodomain maintains an autoinhibited state in which the TMs are held apart. Ligand binding releases this constraint, allowing TM association and unleashing an intrinsic propensity of the intracellular regions to autophosphorylate. Enzymatic studies of full-length and kinase-containing fragments show phosphorylated IGF1R is fully active independent of ligand and the extracellular-TM regions. The key step triggered by ligand binding is thus autophosphorylation.
0000
Cao, Jia; Peng, Jinghua; An, Hongying; He, Qiyi; Boronina, Tatiana; Guo, Shaodong; White, Morris F; Cole, Philip A; He, Ling
Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity Journal Article
In: Nat Commun, vol. 8, no. 1, pp. 131, 0000, ISSN: 2041-1723.
Abstract | Links | BibTeX | Tags: Animals, Cell Line, E1A-Associated p300 Protein, Endoplasmic Reticulum Stress, Endotoxemia, Gene Expression Profiling, Immunoblotting, Inbred C57BL, Insulin, Insulin Resistance, Lipopolysaccharides, Liver, Male, Membrane Proteins, Mice, Obese, Obesity, Protein-Serine-Threonine Kinases, Receptor, Signal Transduction, Tumor, X-Box Binding Protein 1
@article{1299941,
title = {Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity},
author = {Jia Cao and Jinghua Peng and Hongying An and Qiyi He and Tatiana Boronina and Shaodong Guo and Morris F White and Philip A Cole and Ling He},
doi = {10.1038/s41467-017-00163-w},
issn = {2041-1723},
journal = {Nat Commun},
volume = {8},
number = {1},
pages = {131},
abstract = {Diabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation. An elevated plasma concentration of lipopolysaccharide (LPS) caused by increased intestinal permeability during diet-induced obesity promotes insulin resistance in mice. Here, we show that LPS induces endoplasmic reticulum (ER) stress and protein levels of P300, an acetyltransferase involved in glucose production. In high-fat diet fed and genetically obese ob/ob mice, P300 translocates from the nucleus into the cytoplasm of hepatocytes. We also demonstrate that LPS activates the transcription factor XBP1 via the ER stress sensor IRE1, resulting in the induction of P300 which, in turn, acetylates IRS1/2, inhibits its association with the insulin receptor, and disrupts insulin signaling. Pharmacological inhibition of P300 acetyltransferase activity by a specific inhibitor improves insulin sensitivity and decreases hyperglycemia in obese mice. We suggest that P300 acetyltransferase activity may be a promising therapeutic target for the treatment of obese patients.Elevated plasma LPS levels have been associated with insulin resistance. Here Cao et al. show that LPS induces ER stress and P300 activity via the XBP1/IRE1 pathway. P300 acetylates IRS1/2 and inhibits its binding with the insulin receptor. The consequent impairment of insulin signaling can be rescued by pharmacological inhibition of P300.},
keywords = {Animals, Cell Line, E1A-Associated p300 Protein, Endoplasmic Reticulum Stress, Endotoxemia, Gene Expression Profiling, Immunoblotting, Inbred C57BL, Insulin, Insulin Resistance, Lipopolysaccharides, Liver, Male, Membrane Proteins, Mice, Obese, Obesity, Protein-Serine-Threonine Kinases, Receptor, Signal Transduction, Tumor, X-Box Binding Protein 1},
pubstate = {published},
tppubtype = {article}
}
Diabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation. An elevated plasma concentration of lipopolysaccharide (LPS) caused by increased intestinal permeability during diet-induced obesity promotes insulin resistance in mice. Here, we show that LPS induces endoplasmic reticulum (ER) stress and protein levels of P300, an acetyltransferase involved in glucose production. In high-fat diet fed and genetically obese ob/ob mice, P300 translocates from the nucleus into the cytoplasm of hepatocytes. We also demonstrate that LPS activates the transcription factor XBP1 via the ER stress sensor IRE1, resulting in the induction of P300 which, in turn, acetylates IRS1/2, inhibits its association with the insulin receptor, and disrupts insulin signaling. Pharmacological inhibition of P300 acetyltransferase activity by a specific inhibitor improves insulin sensitivity and decreases hyperglycemia in obese mice. We suggest that P300 acetyltransferase activity may be a promising therapeutic target for the treatment of obese patients.Elevated plasma LPS levels have been associated with insulin resistance. Here Cao et al. show that LPS induces ER stress and P300 activity via the XBP1/IRE1 pathway. P300 acetylates IRS1/2 and inhibits its binding with the insulin receptor. The consequent impairment of insulin signaling can be rescued by pharmacological inhibition of P300.