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

Yupeng Wang,Bing Su,Zhengui Xia

doi:10.1074/jbc.m605503200

Abstract

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.

Highlights

The extracellular signal-regulated kinase 5 (ERK5)2 or big MAP kinase 1 (BMK1) is a member of the mitogen-activated protein (MAP) kinase family that includes ERK1/2, p38, and N-terminal c-Jun protein kinase (JNK) [1, 2]
We examined the kinetics for ERK5 activation after brain-derived neurotrophic factor (BDNF) treatment and compared it to ERK1/2 activation
MEK5 was the only upstream regulator of ERK5 identified in central nervous system neurons [4]

Summary

Introduction

The extracellular signal-regulated kinase 5 (ERK5) or big MAP kinase 1 (BMK1) is a member of the mitogen-activated protein (MAP) kinase family that includes ERK1/2, p38, and N-terminal c-Jun protein kinase (JNK) [1, 2]. We discovered that ERK5 expression in the brain is maximal during early embryonic development and declines as the brain matures [16]. ERK5 and ERK5-regulated MEF2 gene expression contribute to BDNF-promoted survival of developing, but not mature neurons cultured from the cortex and cerebellum [16, 17]. The only known signaling molecule mediating ERK5 activation in central nervous system neurons is MEK5 [16, 17]. We used primary cultured cortical neurons from embryonic day (E) 16 –17 rodents to investigate signaling pathways that mediate BDNF stimulation of ERK5. Our data strongly implicate Rap and MEKK2 in BDNF stimulation of ERK5

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