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Published online May 29, 2007
doi:10.1083/jcb.200609017
The Journal of Cell Biology, Vol. 177, No. 5, 817-827
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Aoki et al.
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Article

 An essential role for the SHIP2-dependent negative feedback loop in neuritogenesis of nerve growth factor–stimulated PC12 cells

Kazuhiro Aoki1, Takeshi Nakamura1, Takanari Inoue2, Tobias Meyer2, and Michiyuki Matsuda1

1 Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
2 Department of Molecular Pharmacology, Stanford University, Stanford, CA 94305

Correspondence to Takeshi Nakamura: tnakamr{at}path1.med.kyoto-u.ac.jp

The local accumulation of phosphatidylinositol (3,4,5) trisphosphate (PIP3) and resulting activation of Rac1/Cdc42 play a critical role in nerve growth factor (NGF)–induced neurite outgrowth. To further explore the mechanism, we visualized PIP3, phosphatidylinositol (3,4) bisphosphate, and Rac1/Cdc42 activities by fluorescence resonance energy transfer (FRET) imaging in NGF-stimulated PC12 cells. Based on the obtained FRET images, and with the help of in silico kinetic reaction model, we predicted that PI-5-phosphatase negatively regulates PIP3 upon NGF stimulation. In agreement with this model, depletion of Src homology 2 domain–containing inositol polyphosphate 5-phosphatase 2 (SHIP2) markedly potentiated NGF-induced Rac1/Cdc42 activation and PIP3 accumulation and considerably increased the number and the length of neurites in phosphate and tensin homologue–depleted PC12 cells. Further refinement of the computational model predicted Rac1 regulation of PI3-kinase and SHIP2, which was also validated experimentally. We propose that the SHIP2-mediated negative feedback on PIP3 coordinately works with the PI3-kinase–mediated positive feedback to form an initial protrusive pattern and, later, to punctuate the PIP3 accumulation to maintain proper neurite outgrowth.

Abbreviations used in this paper: FRET, fluorescence resonance energy transfer; GAP, GTPase-activating protein; GRP, general receptor of phosphoinositides; PH, pleckstrin homology; PI(3,4)P2, phosphatidylinositol (3,4) bisphosphate; PI3-kinase, phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol (3,4,5) trisphosphate; PTEN, phosphate and tensin homologue; SHIP2, Src homology 2 domain–containing inositol phosphatase 2; shRNA, short hairpin RNA.


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