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The neurosecretory vesicle protein phogrin is a phosphatidylinositol phosphatase whose activity regulates insulin secretion
Author(s) -
Caromile Leslie Ann,
Oganesian Anush,
Coats Scott A.,
Seifert Ronald A.,
BowenPope Daniel F.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1131-c
Subject(s) - phosphatidylinositol , secretion , insulin , secretory pathway , vesicle , protein tyrosine phosphatase , secretory vesicle , tyrosine phosphorylation , phosphatase , endocrinology , medicine , secretory protein , phosphorylation , microbiology and biotechnology , chemistry , exocytosis , biology , biochemistry , membrane , golgi apparatus , endoplasmic reticulum
Phogrin (NE‐6, IA‐2β) is a 64KD protein present on insulin‐containing secretory granules in pancreatic beta cells. Auto‐antibodies against Phogrin are common in pre‐diabetics and are used clinically to diagnose a pre‐diabetic state. Although Phogrin has sequence homology to tyrosine phosphatases, no enzymatic activity has been reported. We therefore tested Phogrin for enzymatic activity, determined its preferred substrates and tested for a possible role in insulin secretion. We found that Phogrin dephosphorylates inositol phospholipids, including phosphatidylinositol–4,5‐bisphospate, PI(4,5)P2, which is known to regulate membrane vesicle dynamics during insulin secretion. Additionally, PKA‐dependent phosphorylation of Phogrin decreases its phosphatidylinositol phosphatase activity by 80%. Phogrin overexpression in rat beta cells reduced plasma membrane levels of PI(4,5)P2 by 50% and decreased glucose stimulated insulin secretion by 80%. Our results suggest that Phogrin is a phosphatidylinositol phosphatase that contributes to differential expression of PI(4,5)P2 in secretory vesicles and the plasma membrane and thereby helps regulate insulin secretion. These results identify steps at which the secretory pathway for insulin release may be mis‐regulated in diabetes and/or manipulated therapeutically. Source of funding: JDRF 1‐2006‐841, NIH T32 HL07312.