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MBC in Press, published online ahead of print November 9, 2005
Mol. Biol. Cell 10.1091/mbc.E05-05-0469

A more recent version of this article appeared on February 1, 2006
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Submitted on May 31, 2005
Revised on October 7, 2005
Accepted on November 2, 2005

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

Lisa M. Ooms,* Clare G. Fedele,* Megan V. Astle,* Ivan Ivetac,* Vanessa Cheung,* Richard B. Pearson,{dagger} Meredith J. Layton,{ddagger} Ariel Forrai,* Harshal H. Nandurkar,* and Christina A. Mitchell*

*Department of Biochemistry and Molecular Biology, Monash University, Clayton 3800, Victoria, Australia; {dagger}Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne 8006, Victoria, Australia; {ddagger}Ludwig Institute of Medical Research, Joint Proteomics Research Laboratory, Parkville 3050, Victoria, Australia

Monitoring Editor: John York

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)P3), which localizes and facilitates Akt activation and stimulates GSK-3{beta} inactivation, promoting microtubule polymerization and axon elongation. However, the molecular mechanisms that govern the spatial down-regulation of PtdIns(3,4,5)P3 signaling at the growth cone remain undetermined. The inositol polyphosphate 5-phosphatases (5-phosphatase) hydrolyze the 5-position phosphate from phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) and/or PtdIns(3,4,5)P3. We demonstrate here that PIPP, an uncharacterized 5-phosphatase, hydrolyzes PtdIns(3,4,5)P3 forming PtdIns(3,4)P2, decreasing Ser473-Akt phosphorylation. PIPP is expressed in PC12 cells, localizing to the plasma membrane of undifferentiated cells and the neurite shaft and growth cone of NGF-differentiated neurites. Overexpression of wild-type, but not catalytically-inactive PIPP, in PC12 cells inhibited neurite elongation. Targeted depletion of PIPP using RNA interference (RNAi) resulted in enhanced neurite differentiation, associated with neurite hyper-elongation. Inhibition of PI3-kinase activity prevented neurite hyper-elongation in PIPP-deficient cells. PIPP targeted-depletion resulted in increased phospho-Ser473-Akt and phospho-Ser9-GSK-3{beta}, specifically at the neurite growth cone, and accumulation of PtdIns(3,4,5)P3 at this site, associated with enhanced microtubule polymerization in the neurite shaft. PIPP therefore inhibits PI3-kinase-dependent neurite elongation in PC12 cells, via regulation of the spatial distribution of phospho-Ser473-Akt and phospho-Ser9-GSK-3{beta} signaling.

Address correspondence to: Christina A. Mitchell (Christina.Mitchell{at}med.monash.edu.au)




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