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  Phosphoproteomics Reveals the GSK3-PDX1 Axis as a Key Pathogenic Signaling Node in Diabetic Islets

Sacco, F., Seelig, A., Humphrey, S. J., Krahmer, N., Volta, F., Reggio, A., et al. (2019). Phosphoproteomics Reveals the GSK3-PDX1 Axis as a Key Pathogenic Signaling Node in Diabetic Islets. Cell Metabolism, 29(6), 1422-1432.e3. doi:10.1016/j.cmet.2019.02.012.

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 Creators:
Sacco, Francesca1, Author           
Seelig, Anett2, Author
Humphrey, Sean J.2, Author
Krahmer, Natalie1, Author           
Volta, Francesco2, Author
Reggio, Alessio2, Author
Marchetti, Piero2, Author
Gerdes, Jantje2, Author
Mann, Matthias1, Author           
Affiliations:
1Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              
2external, ou_persistent22              

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Free keywords: PANCREATIC BETA-CELLS; INSULIN-RESISTANCE; TYPE-2; IDENTIFICATION; ASSOCIATION; DYSFUNCTION; PROTEOMICS; GENETICS; OBESITY; GSK-3Cell Biology; Endocrinology & Metabolism;
 Abstract: Progressive decline of pancreatic beta cell function is central to the pathogenesis of type 2 diabetes. Protein phosphorylation regulates glucose-stimulated insulin secretion from beta cells, but how signaling networks are remodeled in diabetic islets in vivo remains unknown. Using high-sensitivity mass spectrometry-based proteomics, we quantified 6,500 proteins and 13,000 phosphopeptides in islets of obese diabetic mice and matched controls, revealing drastic remodeling of key kinase hubs and signaling pathways. Integration with a literature-derived signaling network implicated GSK3 kinase in the control of the beta cell-specific transcription factor PDX1. Deep phosphoproteomic analysis of human islets chronically treated with high glucose demonstrated a conserved glucotoxicity-dependent role of GSK3 kinase in regulating insulin secretion. Remarkably, the ability of beta cells to secrete insulin in response to glucose was rescued almost completely by pharmacological inhibition of GSK3. Thus, our resource enables investigation of mechanisms and drug targets in type 2 diabetes.

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Language(s): eng - English
 Dates: 2019
 Publication Status: Issued
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

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Title: Cell Metabolism
  Other : Cell Metabolism
Source Genre: Journal
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Publ. Info: Cambridge, MA : Cell Press
Pages: - Volume / Issue: 29 (6) Sequence Number: - Start / End Page: 1422 - 1432.e3 Identifier: ISSN: 1550-4131
CoNE: https://pure.mpg.de/cone/journals/resource/111088195284928