ERK5 activation of MEF2-mediated gene expression plays a critical role in BDNF-promoted survival of developing but not mature cortical neurons

Abstract

Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase family whose biological function in the CNS has not been defined. In contrast to ERK1 and ERK2, which are activated by neurotrophins (NTs), cAMP, and neuronal activity in cortical neurons, ERK5 is activated only by NTs. Here, we report that ERK5 expression is high in the brain during early embryonic development but declines as the brain matures to almost undetectable levels by postnatal day (P) 49. Interestingly, expression of a dominant-negative ERK5 blocked brain-derived neurotrophic factor protection against trophic withdrawal in primary cortical neurons cultured from embryonic day (E) 17 but not P0. Furthermore, expression of a dominant-negative ERK5 induced apoptosis in E17 but not P0 cortical neurons maintained in the presence of serum. We also present evidence that ERK5 protection of E17 cortical neurons may be mediated through myocyte enhancer factor 2-induced gene expression. These data suggest that ERK5 activation of myocyte enhancer factor 2-induced gene expression may play an important and novel role in the development of the CNS by mediating NT-promoted survival of embryonic neurons.N eurotrophins (NTs) have profound effects on the development of the CNS and regulate differentiation, survival, and adaptive responses of neurons. For example, NTs protect many types of neurons from apoptosis both during development and in the adult (1-6). Consequently, there is an intense interest in elucidating mechanisms for NT-mediated neuroprotection and its contribution to the development of the CNS. NTs including nerve growth factor, brain-derived neurotrophic factor (BDNF), NT3, NT4͞5, and NT6 bind to and activate specific receptor tyrosine kinases of the Trk family (7,8). Upon binding to and activating Trk, NTs can activate several intracellular signaling transduction systems including the phosphatidylinositol 3-kinase, protein kinase C, and extracellular signal-regulated kinase 1͞2 (ERK1͞2) pathways (8-11).Recently, a new member of the mitogen-activated protein (MAP) kinase family, ERK5 (also known as the big MAP kinase 1 or BMK1) was discovered (12, 13). ERK5 is widely expressed in many tissues including brain. Although ERK5 contains a similar TEY dual-phosphorylation motif as ERK1͞2 and the N-terminal half of ERK5 shares sequence homology with other members of the MAP kinase family, a large C terminus and a unique loop-12 sequence distinguish it from ERK1͞2 and other MAP kinase family members. ERK5 is phosphorylated and activated by MAP kinase kinase (MEK) 5, but not by MEK1 or MEK2 (12,14). MEK5 is specific for ERK5 and does not phosphorylate ERK1͞2, c-Jun N-terminal protein kinase, or p38 MAP kinase (12,14). A number of substrates have been identified for activated ERK5 including myocyte enhancer factor 2C (MEF2C) (15-17). Like ERK1͞2, ERK5 is activated by serum, epidermal growth factor, nerve growth factor, and G protein-coupled receptors (15)(16)(17)(18)(19). In contrast to ERK1 and ERK2, which are activat...

Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques

“…5A,B; Flavell et al 2006;Shalizi et al 2006). Furthermore, expression patterns of two known MEF2A activators, brain-derived neurotrophic factor (BDNF), which is linked to neuronal survival (Liu et al 2003;Shalizi et al 2003), as well as PPP3CB (also known as calcineurin A beta), which is involved in calcium influx-dependent dephosphorylation of MEF2A (McKinsey et al 2002;Shalizi et al 2006), showed human-specific delays consistent with the MEF2A expression profile and the average Figure 4. Regulation of human-specific expression patterns by TFs.…”

p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription

“…Activated ERK1/2 also phosphorylates FOXO3a, leading to the degradation and subsequent inhibition of FOXO3a [38]. ERK5, another member of the MAP kinases that is often pro-survival [39,40], is also a negative regulator of FOXO3a and fibroblasts from ERK5 and MEK5 null mice display increased FOXO3a activity [28]. JNK regulates FOXO3a nuclear translocation in breast cancer cells after paclitaxel treatment [29].…”

Aberrant Extracellular Signal-Regulated Kinase (ERK) 5 Signaling in Hippocampus of Suicide Subjects

“…It is widely expressed in many tissues, with the highest levels in the brain Yan et al, 2003). In neurons, ERK5 is activated by neurotrophins, including brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, and NT-4 (Cavanaugh et al, 2001;Watson et al, 2001;Liu et al, 2003;Shalizi et al, 2003). A number of other extracellular stimuli, such as epidermal growth factor and G-protein-coupled receptors, also activate ERK5 (Kato et al, 1998;Marinissen et al, 1999).…”