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Synergy of glucose and growth hormone signalling in islet cells through ICA512 and STAT5

Nature Cell Biology volume 8, pages 435–445 (2006)Cite this article

Abstract

Nutrients and growth hormones promote insulin production and the proliferation of pancreatic β-cells. An imbalance between ever-increasing metabolic demands and insulin output causes diabetes. Recent evidence indicates that β-cells enhance insulin gene expression depending on their secretory activity. This signalling pathway involves a catalytically inactive receptor tyrosine phosphatase, ICA512, whose cytoplasmic tail is cleaved on glucose-stimulated exocytosis of insulin secretory granules and then moves into the nucleus, where it upregulates insulin transcription. Here, we show that the cleaved cytosolic fragment of ICA512 enhances the transcription of secretory granule genes (including its own gene) by binding to tyrosine phosphorylated signal transducers and activators of transcription (STAT) 5 and preventing its dephosphorylation. Sumoylation of ICA512 by the E3 SUMO ligase PIASy, in turn, may reverse this process by decreasing the binding of ICA512 to STAT5. These findings illustrate how the exocytosis of secretory granules, through a retrograde pathway that sustains STAT activity, converges with growth hormone signalling to induce adaptive changes in β-cells in response to metabolic demands.

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Figure 1: ICA512 enhances the transcription of secretory granule genes.
Figure 2: ICA512 enhances the nuclear levels of STATs.
Figure 3: ICA512 enhances the nuclear levels of PY-STAT5.
Figure 4: ICA512 binds to STAT5b and prevents its dephosphorylation.
Figure 5: ICA512 increases STAT5b activity.
Figure 6: ICA512-mediated binding of PIASy to STAT5.
Figure 7: Sumoylation of ICA512 regulates its binding to STAT5.
Figure 8: STAT5b promotes the transcription of ICA512.

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Acknowledgements

We are grateful to P. De Camilli, M. Matteoli and M. Zerial for critical reading of the manuscript; A. Barthel, R. Grosschedl, R. Janknech, F. White and H. Saitoh for reagents; F. Ehehalt, K. Erdmann and M. Jäger for help in islet isolation; K. Pfriem for excellent assistance; and G. Nikolova and all members of the Solimena lab for advice. This work was supported by funds from the Alexander von Humboldt Foundation, the German Ministry for Education and Research (BMBF), the European Foundation for the Study of Diabetes and the Juvenile Diabetes Research Foundation to M.S., and a MedDrive Grant from the Medical School of Dresden Univsity of Technology to H.M. and M.T.

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Authors and Affiliations

  1. Experimental Diabetology, School of Medicine, Dresden University of Technology, Dresden, 01307, Germany

    Hassan Mziaut, Mirko Trajkovski, Stephan Kersting, Armin Ehninger, Anke Altkrüger & Michele Solimena

  2. Department of Surgery, School of Medicine, Dresden University of Technology, Dresden, 01307, Germany

    Stephan Kersting & Hans-Detlev Saeger

  3. Medical Clinic III, School of Medicine, Dresden University of Technology, Dresden, 01307, Germany

    Michele Solimena

  4. Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, 01307, Germany

    Régis P. Lemaitre & David N. Drechsel

  5. Max Planck Institute for Biochemistry, Martinsried, 82152, Germany

    Darja Schmidt & Stefan Müller

  6. Department of Medicine, Samsung Medical Center, Sungkyunkwan Univ. School of Medicine, Seoul, 135–710, Korea

    Myung-Shik Lee

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Mziaut, H., Trajkovski, M., Kersting, S. et al. Synergy of glucose and growth hormone signalling in islet cells through ICA512 and STAT5. Nat Cell Biol 8, 435–445 (2006). https://doi.org/10.1038/ncb1395

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