Extracellular signal regulated kinase5 (ERK5), also known as BMK1, is an atypical MAPK that is activated in vivo by a variety of stimuli including serum, growth factors (EGF, NGF, BDNF), GPCRs, lysophosphatidic acid, neurotrophins, phorbol ester and cellular stress factors such as oxidative and osmotic shock. MAPK cascades play important roles in many cellular processes including cell proliferation, differentiation, survival and apoptosis. Upstream components of the ERK5 pathway include Ras, MEKK2, MEKK3, MEK5, c-Src and COT. Downstream targets for ERK5 include connexin-43, RSK, and the transcription factors MEF2A, -C, and -D, SAP1A, SGK and PPAR-γ1.Mitogens such as EGF and G-CSF transmit their growth-promoting signals via ERK5. WNK1 is required for activation of ERK5 by EGF. EGF also induces activation of ERK5 via c-Src and Ras. Adaptor protein LAD/TSAd is required for EGF-induced ERK5 activation via c-Src. TSAd increases the binding affinity between MEKK2 and MEK5 and recruits the MEKK2/MEK5 complex to the receptor thus activating ERK5. Cytokines such as LIF and CT1 induce the phosphorylation of GAB1 and SHP2 that leads to the activation of ERK5.
ERK5 is also activated by neurotrophic factors such as BDNF, NGF and NT3/4. NGF-induced activation of ERK5 is mediated via COT or MEKK3 and MEK5. NGF binds to TRKA receptors that get autophosphorylated and internalized into a signaling endosome that is retrogradely transported from the extending axon to the cell where it activates ERK5. ERK5 then initiates a phosphorylation cascade resulting in the activation of the transcription factor CREB through RSK and regulates the transcription of survival and pro-apoptotic genes. ERK5-mediated survival of neurons in the CNS via the activation of transcription factor MEF2 has also been reported. ERK5 is also activated by stress factors like sorbitol, H2O2 and UV irradiation. H2O2 stimulation of ERK5 is mediated via c-Src tyrosine kinase where ERK5 increases MEF2C DNA binding activity which is important for neuronal survival. GPCRs also potently stimulate ERK5 through a mechanism that involves Gαq and Gα13 independently of Rho, Rac1 and CDC42.
Transcription factors such as MEF2C are phosphorylated by ERK5, which enhances its activity and subsequently leads to increased c-Jun expression. Other direct substrates of ERK5 include SAP1, and c-Myc. ERK5-dependent phosphorylation of SAP1 enhances transcription via a serum response element and is responsible for increasing expression of c-Fos. In addition to acting on the c-Fos promoter, the ERK5 signaling pathway stimulates the transcriptional activity of c-Fos and FRA1. Another substrate of ERK5 is SGK where phosphorylation of SGK promotes the entry of cells into S phase in response to growth factors. Other targets of ERK5 include BAD and FoxO3A. FasL-mediated ERK5 activation induces the phosphorylation of BAD and FoxO3A by PKB-independent and PKB-dependent mechanisms, respectively. In both cases, phosphorylation provides a mechanism by which ERK5 sequesters the proteins in the cytoplasm by promoting their interaction with 14-3-3, thereby blocking their apoptotic effect. The potentially crucial role of ERK5 in cancer and heart disease make this cascade highly attractive for the development of new therapeutic strategies to treat pathological conditions that are resistant to current therapies.