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The Journal of Neuroscience, May 20, 2009, 29(20):6649-6662; doi:10.1523/JNEUROSCI.0927-09.2009

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Cellular/Molecular
Inactivation of Ras by p120GAP via Focal Adhesion Kinase Dephosphorylation Mediates RGMa-Induced Growth Cone Collapse

Mitsuharu Endo and Toshihide Yamashita

Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan

Correspondence should be addressed to either of the following: Mitsuharu Endo, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan, Email: mendo{at}med.kobe-u.ac.jp; or Toshihide Yamashita, Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan, Email: yamashita{at}molneu.med.osaka-u.ac.jp

The repulsive guidance molecule RGMa performs several functions in the developing and adult CNSs. RGMa, through its receptor neogenin, induces growth cone collapse and neurite outgrowth inhibition. Here, we demonstrate that RGMa binding to neogenin leads to the inactivation of Ras, which is required for the RGMa-mediated repulsive function in cortical neurons. This signal transduction is mediated by the Ras-specific GTPase-activating protein (GAP) p120GAP. The SH2 domain of p120GAP interacts with focal adhesion kinase (FAK), which is phosphorylated at Tyr-397. When the cells are stimulated with RGMa, FAK undergoes dephosphorylation at Tyr-397 and is dissociated from p120GAP, and this dissociation is followed by an increase in the interaction between p120GAP and GTP-Ras. In addition, the knockdown of p120GAP prevents RGMa-induced growth cone collapse and neurite outgrowth inhibition. Furthermore, RGMa stimulation induces Akt inactivation through p120GAP, and the expression of the constitutively active Akt prevents RGMa-induced growth cone collapse. Thus, RGMa binding to neogenin regulates p120GAP activity through FAK Tyr-397 dephosphorylation, leading to the inactivation of Ras and its downstream effector Akt, and this signal transduction plays a role in the RGMa-mediated repulsive function.

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Received Feb. 23, 2009; revised April 7, 2009; accepted April 17, 2009.

Correspondence should be addressed to either of the following: Mitsuharu Endo, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan, Email: mendo{at}med.kobe-u.ac.jp; or Toshihide Yamashita, Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan, Email: yamashita{at}molneu.med.osaka-u.ac.jp

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