title: Synergy of glucose and growth hormone signalling in islet cells through ICA512 and STAT5.
abstract: Nutrients and growth hormones promote insulin production and the proliferation of pancreatic beta-cells. An imbalance between ever-increasing metabolic demands and insulin output causes diabetes. Recent evidence indicates that beta-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 beta-cells in response to metabolic demands.
authors.affiliation: Experimental Diabetology, School of Medicine, Dresden University of Technology, Dresden 01307, Germany.
authors.forename: Hassan
authors.initials: H
authors.lastname: Mziaut
authors.forename: Mirko
authors.initials: M
authors.lastname: Trajkovski
authors.forename: Stephan
authors.initials: S
authors.lastname: Kersting
authors.forename: Armin
authors.initials: A
authors.lastname: Ehninger
authors.forename: Anke
authors.initials: A
authors.lastname: Altkrüger
authors.forename: Régis P
authors.initials: RP
authors.lastname: Lemaitre
authors.forename: Darja
authors.initials: D
authors.lastname: Schmidt
authors.forename: Hans-Detlev
authors.initials: HD
authors.lastname: Saeger
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.forename: David N
authors.initials: DN
authors.lastname: Drechsel
authors.forename: Stefan
authors.initials: S
authors.lastname: Müller
authors.forename: Michele
authors.initials: M
authors.lastname: Solimena
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D005947:Glucose / Q000494:pharmacology*; D013006:Growth Hormone / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011485:Protein Binding; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D022142:Secretory Vesicles / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D001324:Autoantigens; D008565:Membrane Proteins; D050828:Protein Inhibitors of Activated STAT; D050799:STAT5 Transcription Factor; D025841:Small Ubiquitin-Related Modifier Proteins; D013006:Growth Hormone; D017027:Protein Tyrosine Phosphatases; C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005947:Glucose