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

Hassan Mziaut¹, Mirko Trajkovski¹, Stephan Kersting^1, 2, Armin Ehninger¹, Anke Altkrüger¹, Régis P. Lemaitre⁴, Darja Schmidt⁵, Hans-Detlev Saeger², Myung-Shik Lee⁶, David N. Drechsel⁴, Stefan Müller⁵ & Michele Solimena^1, 3

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

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

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

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

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

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

Nutrients and growth hormones promote insulin production and the proliferation of pancreatic -cells. An imbalance between ever-increasing metabolic demands and insulin output causes diabetes. Recent evidence indicates that -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 -cells in response to metabolic demands.

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