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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Francesca Sacco & Sean J. Humphrey & Jürgen Cox & Marcel Mischnik & Anke Schulte & Thomas Klabunde & Matthias Schäfer & Matthias Mann, 2016. "Glucose-regulated and drug-perturbed phosphoproteome reveals molecular mechanisms controlling insulin secretion," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13250
    DOI: 10.1038/ncomms13250
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    Cited by:

    1. Konxhe Kulaj & Alexandra Harger & Michaela Bauer & Özüm S. Caliskan & Tilak Kumar Gupta & Dapi Menglin Chiang & Edward Milbank & Josefine Reber & Angelos Karlas & Petra Kotzbeck & David N. Sailer & Fr, 2023. "Adipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Sarah E. Conduit & Wayne Pearce & Amandeep Bhamra & Benoit Bilanges & Laura Bozal-Basterra & Lazaros C. Foukas & Mathias Cobbaut & Sandra D. Castillo & Mohammad Amin Danesh & Mahreen Adil & Arkaitz Ca, 2024. "A class I PI3K signalling network regulates primary cilia disassembly in normal physiology and disease," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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