The Inositol Polyphosphate 5-Phosphatase, PIPP, Is a Novel Regulator of Phosphoinositide 3-Kinase-dependent Neurite Elongation

• DOI: 10.1091/mbc.e05-05-0469
• Publication Date: 2005-11-10T01:24:11Z
• Authors: Lisa M. Ooms; Clare G. Fedele; Megan V. Astle; Ivan Ivetac; Vanessa Cheung; Richard B. Pearson; Meredith J. Layton; Ariel Forrai; Harshal H. Nandurkar; Christina A. Mitc...
• Keywords: Neurite; Growth cone

The spatial activation of phosphoinositide 3-kinase (PI3-kinase) signaling at the axon growth cone generates phosphatidylinositol 3,4,5 trisphosphate (PtdIns(3,4,5)P 3 ), which localizes and facilitates Akt stimulates GSK-3β inactivation, promoting microtubule polymerization elongation. However, molecular mechanisms that govern down-regulation PtdIns(3,4,5)P remain undetermined. inositol polyphosphate 5-phosphatases (5-phosphatase) hydrolyze 5-position phosphate from 4,5 bisphosphate (PtdIns(4,5)P 2 ) and/or . We demonstrate here PIPP, an uncharacterized 5-phosphatase, hydrolyzes forming PtdIns(3,4)P , decreasing Ser473-Akt phosphorylation. PIPP is expressed in PC12 cells, localizing to plasma membrane undifferentiated cells neurite shaft NGF-differentiated neurites. Overexpression wild-type, but not catalytically inactive inhibited Targeted depletion using RNA interference (RNAi) resulted enhanced differentiation, associated with hyperelongation. Inhibition PI3-kinase activity prevented hyperelongation PIPP-deficient cells. targeted-depletion increased phospho-Ser473-Akt phospho-Ser9-GSK-3β, specifically cone, accumulation this site, shaft. therefore inhibits PI3-kinase-dependent elongation via regulation distribution phospho-Ser9-GSK-3β signaling.