Glucose-regulated and drug-perturbed phosphoproteome reveals molecular mechanisms controlling insulin secretion

Francesca Sacco, Sean J. Humphrey, Jürgen Cox, Marcel Mischnik, Anke Schulte, Thomas Klabunde, Matthias Schäfer and Matthias Mann ()
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Francesca Sacco: Max Planck Institute of Biochemistry
Sean J. Humphrey: Max Planck Institute of Biochemistry
Jürgen Cox: Max Planck Institute of Biochemistry
Marcel Mischnik: Sanofi Aventis Deutschland GmbH, R&D, LGCR, SDI, Bioinformatics
Anke Schulte: Sanofi Aventis Deutschland GmbH, R&TM, Islet Biology
Thomas Klabunde: Sanofi Aventis Deutschland GmbH, R&D, LGCR, SDI, Bioinformatics
Matthias Schäfer: Sanofi Aventis Deutschland GmbH, R&TM, Islet Biology
Matthias Mann: Max Planck Institute of Biochemistry

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Insulin-secreting beta cells play an essential role in maintaining physiological blood glucose levels, and their dysfunction leads to the development of diabetes. To elucidate the signalling events regulating insulin secretion, we applied a recently developed phosphoproteomics workflow. We quantified the time-resolved phosphoproteome of murine pancreatic cells following their exposure to glucose and in combination with small molecule compounds that promote insulin secretion. The quantitative phosphoproteome of 30,000 sites clustered into three main groups in concordance with the modulation of the three key kinases: PKA, PKC and CK2A. A high-resolution time course revealed key novel regulatory sites, revealing the importance of methyltransferase DNMT3A phosphorylation in the glucose response. Remarkably a significant proportion of these novel regulatory sites is significantly downregulated in diabetic islets. Control of insulin secretion is embedded in an unexpectedly broad and complex range of cellular functions, which are perturbed by drugs in multiple ways.

Date: 2016
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DOI: 10.1038/ncomms13250

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