ICA512 luminal domain: unravelling its role in insulinoma and pancreaticbeta cells.

JUHA M. TORKKO ; M. EVANGELINA PRIMO; RONALD DIRKX; ANNE FRIEDRICH; ANTJE VIEHRIG; ELISA VERGUN; MAURICIO SICA; MARIO ERMACORA ; MICHALE SOLIMENA

Berlin

Congreso; 48th Annual Meeting of the european Association for the study of diabetes; 2012

European Association for the Study of Diabetes.

ICA512/IA-2/RPTPN is a catalytically inactive receptor tyrosine phosphatase enriched in the membrane of insulin secretory granules (ISGs) of pancreatic beta cells. ICA512 null mice previously showed that upon insulin SG exocytosis, ICA512 is transiently inserted into the plasma membrane, where its cytoplasmic tail is cleaed by calpain. The resulting cytosolic fragment may enhance insulin secretion by activating expression of genes involved in insulin SG biogenesis and/or in beta-ell proliferation. This fragmen t can also act on dislocation of the actin cytoskeleton residing insulin SGs, thus enabling their mobilization and recruitment for exocytosis. Structural studies have revealed that the mature ectodomain (ME ICA512) contains a SEA domain, as commonly found in mucins. ME adopts different dimeric structures in vitro in crystal and also in solution, and ws found to display self-proteolytic activity similar other SEA-domain like fold proteins, concerned as a mechanism critical for the protein functional maturation.