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J. Biol. Chem., Vol. 281, Issue 8, 4771-4778, February 24, 2006

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Combined Signaling through ERK, PI3K/AKT, and RAC1/p38 Is Required for Met-triggered Cortical Neuron Migration^*

From the Inserm UMR623, Developmental Biology Institute of Marseille (CNRS-INSERM-UniversitédelaMéditerranée), Campus de Luminy-Case 907, 13288 Marseille Cedex 09, France

Cell migration is a complex biological process playing a key role in physiological and pathological conditions. During central nervous system development, positioning and function of cortical neurons is tightly regulated by cell migration. Recently, signaling events involving the urokinase-type plasminogen activator receptor, which is a key regulator for the activation of hepatocyte growth factor (HGF), have been implicated in modulating cortical neuron migration. However, the intracellular pathways controlling neuronal migration triggered by the HGF receptor Met have not been elucidated. By combining pharmacological and genetic approaches, we show here that the Ras/ERK pathway and phosphatidylinositol 3-kinase (PI3K) are both required for cortical neuron migration. By dissecting the downstream signals necessary for this event, we found that Rac1/p38 and Akt are required, whereas the c-Jun N-terminal kinase (JNK) and mTOR/p70^s6k pathways are dispensable. This study demonstrates that concomitant activation of the Ras/ERK, PI3K/Akt, and Rac1/p38 pathways is required to achieve full capacity of cortical neurons to migrate upon HGF stimulation.

Received for publication, July 28, 2005 , and in revised form, November 21, 2005.

^* This work was supported in part by the "Association Française contre les Myopathies" (AFM), the "Fondation pour la Recherche Médicale" (FRM), the "Association pour la Recherche sur le Cancer" (ARC), the "Fondation de France" (FdF), and an Action Concertée Incitative (ACI) grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3 and supplemental references.

This article was selected as a Paper of the Week.

¹ Present address: INSERM EMI 0104, CEA Grenoble, 17 rue des Martyrs, 38054 Grenoble Cedex 09, France.

² Supported by a grant from the Marie Curie Host Fellowship for the Research Training Network (MRTN-CT-2003–504636).

³ These authors contributed equally to this work.

⁴ To whom correspondence should be addressed. Tel.: 33-4-91-26-97-78; Fax: 33-4-91-26-97-57; E-mail: lamballe{at}ibdm.univ-mrs.fr.

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