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9 results on '"Sharfi, Hadar"'

4. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis

Author

Locasale, Jason W, Grassian, Alexandra R, Melman, Tamar, Lyssiotis, Costas A, Mattaini, Katherine R, Bass, Adam J, Heffron, Gregory, Metallo, Christian M, Muranen, Taru, Sharfi, Hadar, Sasaki, Atsuo T, Anastasiou, Dimitrios, Mullarky, Edouard, Vokes, Natalie I, Sasaki, Mika, Beroukhim, Rameen, Stephanopoulos, Gregory, Ligon, Azra H, Meyerson, Matthew, Richardson, Andrea L, Chin, Lynda, Wagner, Gerhard, Asara, John M, Brugge, Joan S, Cantley, Lewis C, and Vander Heiden, Matthew G

Published
2011
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8. Sequential phosphorylation of insulin receptor substrate-2 by glycogen synthase kinase-3 and c-Jun NH2-terminal kinase plays a role in hepatic insulin signaling.

Author

Sharfi, Hadar and Eldar-Finkelman, Hagit

Subjects
*SERINE, *PHOSPHORYLATION, *GLYCOGEN synthase kinase-3, *INSULIN, *LIVER cells, *GENETIC mutation
Abstract

Serine phosphorylation of insulin receptor substrate (IRS) proteins is a potential inhibitory mechanism in insulin signaling. Here we show that IRS-2 is phosphorylated by glycogen synthase kinase (GSK)-3. Phosphorylation by GSK-3 requires prior phosphorylation of its substrates, prompting us to identify the "priming kinase." It was found that the stress activator anisomycin enhanced the ability of GSK-3 to phosphorylate IRS-2. Use of a selective c-Jun NH2-terminal kinase (JNK) inhibitor and cells overexpressing JNK implicated JNK as the priming kinase. This allowed us to narrow down the number of potential GSK-3 phosphorylation sites within IRS-2 to four regions that follow the motif SXXXSP. IRS-2 deletion mutants enabled us to localize the GSK-3 and iNK phosphorylation sites to serines 484 and 488, respectively. Mutation at serine 488 reduced JNK phosphorylation of IRS-2, and mutation of each site separately abolished GSK-3 phosphorylation of IRS-2. Treatment of H4IIE liver cells with anisomycin inhibited insulin-induced tyrosine phosphorylation of IRS-2; inhibition was reversed by pretreatment with the JNK and GSK-3 inhibitors. Moreover, overexpression of iNK and GSK-3 in H4IIE cells reduced insulin-induced tyrosine phosphorylation of IRS-2 and its association with the p85 regulatory subunit of phosphatidylinositol 3-kinase. Finally, both GSK-3 and JNK are abnormally upregulated in the diabetic livers of ob/obmice. Together, our data indicate that IRS-2 is sequentially phosphorylated by iNK and GSK-3 at serines 484/488 and provide evidence for their inhibitory role in hepatic insulin signaling. [ABSTRACT FROM AUTHOR]

Published
2008
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9. Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice

Author

Hadar Sharfi, Hwi Jin Ko, Barbara B. Kahn, Ken S. Lau, Richard Bonneau, Tejia Zhang, Michael B. Yaffe, Randall H. Friedline, Kevin M. Haigis, Timothy G. Curran, Alan Saghatelian, Emily R. Miraldi, Douglas A. Lauffenburger, Hannah Johnson, Benjamin G. Neel, Jason K. Kim, Forest M. White, Massachusetts Institute of Technology. Computational and Systems Biology Program, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Miraldi, Emily Rae, Sharfi, Hadar, Johnson, Hannah, Lau, Ken S., Curran, Timothy G., Yaffe, Michael B., Lauffenburger, Douglas A., and White, Forest M.

Subjects
Male, Phosphatase, Biophysics, Protein tyrosine phosphatase, Biology, Proteomics, Models, Biological, Biochemistry, Article, Mice, Insulin resistance, Tandem Mass Spectrometry, medicine, Animals, Metabolic Syndrome, Mice, Knockout, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Lipid metabolism, Lipid Metabolism, medicine.disease, Phenotype, Liver, Multivariate Analysis, Regression Analysis, Phosphorylation, Metabolic syndrome, hormones, hormone substitutes, and hormone antagonists
Abstract

Metabolic syndrome describes a set of obesity-related disorders that increase diabetes, cardiovascular, and mortality risk. Studies of liver-specific protein-tyrosine phosphatase 1b (PTP1b) deletion mice (L-PTP1b[superscript −/−]) suggest that hepatic PTP1b inhibition would mitigate metabolic-syndrome through amelioration of hepatic insulin resistance, endoplasmic-reticulum stress, and whole-body lipid metabolism. However, the altered molecular-network states underlying these phenotypes are poorly understood. We used mass spectrometry to quantify protein-phosphotyrosine network changes in L-PTP1b[superscript −/−] mouse livers relative to control mice on normal and high-fat diets. We applied a phosphosite-set-enrichment analysis to identify known and novel pathways exhibiting PTP1b- and diet-dependent phosphotyrosine regulation. Detection of a PTP1b-dependent, but functionally uncharacterized, set of phosphosites on lipid-metabolic proteins motivated global lipidomic analyses that revealed altered polyunsaturated-fatty-acid (PUFA) and triglyceride metabolism in L-PTP1b[superscript −/−] mice. To connect phosphosites and lipid measurements in a unified model, we developed a multivariate-regression framework, which accounts for measurement noise and systematically missing proteomics data. This analysis resulted in quantitative models that predict roles for phosphoproteins involved in oxidation–reduction in altered PUFA and triglyceride metabolism., Pfizer Inc. (grant), National Institutes of Health (U.S.) (grant 5R24DK090963), National Institutes of Health (U.S.) (grant U54-CA112967), National Institutes of Health (U.S.) (grant CA49152 R37), National Institutes of Health (U.S.) (grant R01-DK080756), National Mouse Metabolic Phenotyping Center at UMASS (Grant (U24-DK093000)), National Science Foundation (U.S.) (Graduate Research Fellowship)

Published
2013
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