Dephosphorylation of beta 2-syntrophin and Ca2+/mu-calpain-mediated cleavage of ICA512 upon stimulation of insulin secretion

Islet cell autoantigen (ICA) 512 is a receptor-tyrosine phosphatase-like pr otein associated with the secretory granules of neuroendocrine cells, inclu ding pancreatic beta -cells. Binding of its cytoplasmic tail to beta2-syntr ophin suggests that ICA512 connects secretory granules to the utrophin comp lex and the actin cytoskeleton. Here we show that stimulation of insulin se cretion from INS-1 cells triggers the biosynthesis of pro-ICA512 and the de gradation of its mature form. Inhibition of calpain, which is activated upo n stimulation of insulin secretion, prevents the Ca2+-dependent proteolysis of ICA512. In vitro R-calpain cleaves ICA512 between a putative PEST domai n and the beta2-syntrophin binding site, whereas binding of ICA512 to beta2 -syntrophin protects the former from cleavage. beta2-syntrophin and its F-a ctin-binding protein utrophin are enriched in subcellular fractions contain ing secretory granules. ICA512 preferentially binds phospho-beta2-syntrophi n and stimulation of insulin secretion induces the Ca2+- dependent, okadaic acid-sensitive dephosphorylation of beta2-syntrophin. Similarly to calpept in, okadaic acid inhibits ICA512 proteolysis and insulin secretion. Thus, s timulation of insulin secretion might promote the mobilization of secretory granules by inducing the dissociation of ICA512 from beta2-syntrophin-utro phin complexes and the cleavage of the ICA512 cytoplasmic tail by mu -calpa in.