Abstract
Islet cell autoantigen 512 (ICA512)/IA-2 is a receptor tyrosine phosphatase-like protein associated with the insulin secretory granules (SGs) of pancreatic beta-cells. Here, we show that exocytosis of SGs and insertion of ICA512 in the plasma membrane promotes the Ca(2+)-dependent cleavage of ICA512 cytoplasmic domain by mu-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 beta-cells, whose impaired insulin production and secretion causes diabetes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoantigens / metabolism*
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Calpain / pharmacology
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Cell Line
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Cell Nucleus / metabolism*
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Cytoplasmic Granules / drug effects
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Cytoplasmic Granules / metabolism*
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Cytosol / metabolism
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Exocytosis / physiology*
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Female
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Humans
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Insulin / biosynthesis*
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Insulin / genetics
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Insulin / metabolism
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Insulin Secretion
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Islets of Langerhans / metabolism*
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Membrane Proteins / drug effects
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Membrane Proteins / metabolism*
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Peptide Fragments / metabolism
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Protein Tyrosine Phosphatases / drug effects
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Protein Tyrosine Phosphatases / metabolism*
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Rats
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Rats, Wistar
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Receptor-Like Protein Tyrosine Phosphatases, Class 2
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Receptor-Like Protein Tyrosine Phosphatases, Class 8
Substances
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Autoantigens
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Insulin
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Membrane Proteins
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Peptide Fragments
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PTPRN protein, human
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Protein Tyrosine Phosphatases
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Ptprn protein, rat
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Receptor-Like Protein Tyrosine Phosphatases, Class 2
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Receptor-Like Protein Tyrosine Phosphatases, Class 8
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Calpain
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mu-calpain