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Published online 13 December 2004. doi:10.1083/jcb.200408172
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 6, 1063-1074
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Article

Nuclear translocation of an ICA512 cytosolic fragment couples granule exocytosis and insulin expression in ß-cells



Mirko Trajkovski1, Hassan Mziaut1, Anke Altkrüger1, Joke Ouwendijk1, Klaus-Peter Knoch1, Stefan Müller2, and Michele Solimena1

1 Experimental Diabetology, Carl Gustav Carus Medical School, Dresden University of Technology, Dresden 01307, Germany
2 Department of Molecular Cell Biology, Max Planck Institute for Biochemistry, Martinsried 82152, Germany

Correspondence to Michele Solimena: michele.solimena{at}mailbox.tu-dresden.de

Islet cell autoantigen 512 (ICA512)/IA-2 is a receptor tyrosine phosphatase-like protein associated with the insulin secretory granules (SGs) of pancreatic ß-cells. Here, we show that exocytosis of SGs and insertion of ICA512 in the plasma membrane promotes the Ca2+-dependent cleavage of ICA512 cytoplasmic domain by µ-calpain. This cleavage occurs at the plasma membrane and generates an ICA512 cytosolic fragment that is targeted to the nucleus, where it binds the E3-SUMO ligase protein inhibitor of activated signal transducer and activator of transcription-y (PIASy) and up-regulates insulin expression. Accordingly, this novel pathway directly links regulated exocytosis of SGs and control of gene expression in ß-cells, whose impaired insulin production and secretion causes diabetes.

Abbreviations used in this paper: APP, amyloid precursor protein; CPE, carboxypeptidase E; FRET, fluorescence resonance energy transfer; ICA512, Islet Cell Autoantigen 512; ICA512-CCF, ICA512-cleaved cytosolic fragment; ICA512-TMF, ICA512-transmembrane fragment; INS-1, insulinoma cells-1; PIAS, protein inhibitor of activated STAT; PTP, protein tyrosine phosphatase; SG, secretory granule; siRNA, short-interfering RNA; STAT, signal transducer and activator of transcription.


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