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The neurosecretory vesicle protein Phogrin is a phosphatidylinositol phosphatase whose activity regulates insulin secretion

Phogrin (IA‐2β) is a 64KD protein localized to the insulin‐containing dense‐core vesicles (DCV) of 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 report here that Phogrin is able to dephosphorylate specific inositol phospholipids, including PI(3)P and PI(4,5)P2 but not PI(3,4,5)P3. The PIPase activity of Phogrin is low but measurable when a catalytic domain fusion protein is assayed in solution against soluble short‐chain PIPs. Interestingly, when expressed and assayed as a transmembrane protein, Phogrin's in vitro PIPase activity is (100 fold) higher and, when overexpressed in cells, it is able to reduce plasma membrane PI(4,5)P2 levels in a dose‐dependent manner. This activity depends on the catalytic site Cysteine, is inhibited by phosphorylation by PKA, and correlates with inhibition of glucose‐stimulated insulin secretion. Many secretory vesicle‐associated proteins have domains that bind PI(3)P and/or PI(4,5)P2. We propose that Phogrin functions as a phosphatidylinositol phosphatase, that this activity is regulated by phosphorylation by PKA, and plays a role in regulating DCV and plasma membrane PIP content to permit stimulus‐coupled exocytosis of insulin from DCVs.