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J. Biol. Chem., Vol. 281, Issue 47, 35965-35974, November 24, 2006

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Brain-derived Neurotrophic Factor Activates ERK5 in Cortical Neurons via a Rap1-MEKK2 Signaling Cascade^*

Yupeng Wang, Bing Su, and Zhengui Xia^¶1

From the Toxicology Program in the Department of Environmental and Occupational Health Sciences and the ^¶Graduate Program in Neurobiology & Behavior, University of Washington, Seattle, Washington 98195-7234 and the M. D. Anderson Cancer Center, University of Texas, Houston, Texas 77054

The extracellular signal-regulated kinase 5 (ERK5) is activated in neurons of the central nervous system by neurotrophins including brain-derived neurotrophic factor (BDNF). Although MEK5 is known to mediate BDNF stimulation of ERK5 in central nervous system neurons, other upstream signaling components have not been identified. Here, we report that BDNF induces a sustained activation of ERK5 in rat cortical neurons and activates Rap1, a small GTPase, as well as MEKK2, a MEK5 kinase. Our data indicate that activation of Rap1 or MEKK2 is sufficient to stimulate ERK5, whereas inhibition of either Rap1 or MEKK2 attenuates BDNF activation of ERK5. Furthermore, BDNF stimulation of MEKK2 is regulated by Rap1. Our evidence also indicates that Ras and MEKK3, a MEK5 kinase in non-neuronal cells, do not play a significant role in BDNF activation of ERK5. This study identifies Rap1 and MEKK2 as critical upstream signaling molecules mediating BDNF stimulation of ERK5 in central nervous system neurons.

Received for publication, June 8, 2006 , and in revised form, September 22, 2006.

^* This work was supported by Grant AG19193 (to Z. X.) and facilitated by Grant P30 HD02274 from the NICHD, National Institutes of Health. 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. S1 and S2.

¹ To whom correspondence should be addressed: Dept. of Environmental and Occupational Health Sciences, Box 357234, University of Washington, HSB, Rm. F561C, Seattle, WA 98195. E-mail: zxia{at}u.washington.edu.

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