Dephosphorylation of β2-syntrophin and Ca2+/μ-calpain-mediated cleavage of ICA512 upon stimulation of insulin secretion

Tatiana Ort, Sergei Voronov, Jun Guo, Kathleen Zawalich, Stanley C. Froehner, Walter Zawalich, Michele Solimena

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Islet cell autoantigen (ICA) 512 is a receptor-tyrosine phosphatase-like protein associated with the secretory granules of neuroendocrine cells, including pancreatic β-cells. Binding of its cytoplasmic tail to β2-syntrophin suggests that ICA512 connects secretory granules to the utrophin complex and the actin cytoskeleton. Here we show that stimulation of insulin secretion from INS-1 cells triggers the biosynthesis of pro-ICA512 and the degradation of its mature form. Inhibition of calpain, which is activated upon stimulation of insulin secretion, prevents the Ca2+-dependent proteolysis of ICA512. In vitro μ-calpain cleaves ICA512 between a putative PEST domain and the β2-syntrophin binding site, whereas binding of ICA512 to β2-syntrophin protects the former from cleavage. β2-syntrophin and its F-actin-binding protein utrophin are enriched in subcellular fractions containing secretory granules. ICA512 preferentially binds phospho-β2-syntrophin and stimulation of insulin secretion induces the Ca2+dependent, okadaic acid-sensitive dephosphorylation of β2-syntrophin. Similarly to calpeptin, okadaic acid inhibits ICA512 proteolysis and insulin secretion. Thus, stimulation of insulin secretion might promote the mobilization of secretory granules by inducing the dissociation of ICA512 from β2-syntrophin-utrophin complexes and the cleavage of the ICA512 cytoplasmic tail by μ-calpain.

Original languageEnglish
Pages (from-to)4013-4023
Number of pages11
JournalEMBO Journal
Volume20
Issue number15
DOIs
StatePublished - Aug 1 2001

Keywords

  • Actin
  • Diabetes
  • IA-2
  • Secretory granule
  • Tyrosine phosphatase

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