Extracellular signal-regulated kinase 5 (Erk5), which is a member of the mitogen-activated protein kinase (MAPK) family, is phosphorylated by MAPK/Erk kinase-5 (Mek5
) to regulate the function of various cell types.
Biological effects of melatonin on osteoblast/osteoclast cocultures, bone, and quality of life: Implications of a role for MT2 melatonin receptors, MEK1/2, and MEK5
in melatoninmediated osteoblastogenesis.
Gonzalez et al., "MEK5
and ERK5 are mediators of the pro-myogenic actions of IGF-2," Journal of Cell Science, vol.
induces serial assembly of sarcomeres and eccentric cardiac hypertrophy.
and BMK1 are activated sequentially and BMK1 acts on its downstream targets including Mef2C, c-Myc, and possibly Nrf2 (Figure 3).
Though ERK5 has the TEY array, as well as classical ERK1/2 , it is not activated by MAPK kinase (MEK1/2) but is specifically activated by MEK5. Previous reports showed that ERK5 is activated by hyperosmosis or oxidative stress and it is recognized as a stress responder MAPK, similar to JNK and p38MAPK [30, 31].
Kluger et al., "MEK5 is activated by shear stress, activates ERK5 and induces KLF4 to modulate TNF responses in human dermal microvascular endothelial cells," Microcirculation, vol.
For gain of function studies, a constitutively active MEK5 (CA-MEK5) lentivirus was used to activate ERK5.
A specific ERK5 upstream kinase, MEK5, and c-Src tyrosine kinase have both been shown to mediate ERK5 activation in response to oxidative stress.
Although previous studies have shown that proliferation of hematopoietic cells mediated by granulocyte-macrophage colony-stimulating factor (GM-CSF) , proliferation of vascular smooth muscle cells mediated by platelet-derived growth factor (PDGF) , and proliferation of neural stem/progenitor cells mediated by epidermal growth factor (EGF)  are all ERK5-dependent, many other studies using cells from [Erk5.sup.-/-] and [Mek5.sup.-/-] mice have shown that ERK5 and MEK5 are not required for cell cycle progression [16, 29].
Seyfried et al., "Targeted deletion of mek5 causes early embryonic death and defects in the extracellular signal-regulated kinase 5/myocyte enhancer factor 2 cell survival pathway," Molecular and Cellular Biology, vol.