br Diverse functions of ERK pathway Same as the
Diverse functions of ERK pathway Same as the other MAPK cascades, the ERK pathway is activated by several extracellular stimuli and different internal routes. ERK vitally tunes the function of various substrates in all cellular components; the nucleus, cytoplasm, membranes and the cytoskeleton. ERK associated targets range from transcription and transduction agents to the transmembrane proteins cytosolic factors and other cellular kinases. ERK pathway is elaborated in promotion of a varying range of cell functions including differentiation, proliferation, development, and in specific organs regulation of migration, death, survival, morphology and structure, along with oncogenic transformation (Roux and Blenis, 2004; Sacks, 2006). Multiple extracellular stimuli affect the MAPK/ERK pathway and provoke a variety of responses, for example, the activation of MEK/ERK by NGF evokes neuronal Vacuolin-1 differentiation. In contrast, induction of the same MEK/ERK through epidermal growth factor (EGF) results in the proliferation of neural cells. MAPK/ERK signaling specificity is modulated via different mechanisms; i.e. specificity in the membrane receptors of ERK through different receptor-activated pathways. In the signaling kinetic level, different responses take place over alterations in the duration or strength of the enzyme activation and their regulation is generally accomplished by the components of the inhibitory signaling. Furthermore, the integration of several signaling cascades and the specificity of the compartments of the downstream cascades with distinct MAPK-responsive transcription agents are also involved in ERK's cellular functions (Sacks, 2006; Tan and Kim, 1999). The RAS-RAF-MEK-ERK pathway is hyperactivated in a wide range of malignancies. Mutations and aberrations in different compartments of MEK-ERK pathway have important contributions to the development and progression of numerous human tumors. The RAS mutations are appeared in almost 30% of cancers, which cause phosphorylation of RAF and lead to the activation of ERK pathway. It is highly accepted that overactivated MEK-ERK is associated with the oncogenesis of notorious human tumors, indicating that of MEK-ERK pathway as an interesting target for anticancer therapeutics (Samatar and Poulikakos, 2014). ERK cascade has been found to take a part in the glucose transport responses and phosphorylation of the proteins and the consequent accumulation of intracellular ROS, also cause oxidative damages of the metabolic organs. Thus, ERK takes a significant part in oxidative damage associated metabolic diseases such as type 2 diabetes (Natalicchio et al., 2011). ERK is among the main signaling mediators of hyperalgesia and oxidative stress, which are critical factors in development of arthritis and rheumatoid disorders (Blanc et al., 2003; Farzaei et al., 2016b). The neuroprotective potential of ERK in neuronal system has been shown by current cellular and animal studies. The activation of ERK diminishes neuronal damage incurred by ischemia-hypoxia. In neonatal brain, the protective effects of BDNF treatment against ischemic-hypoxic injury is mediated by ERK activation, in contrast, inhibition of ERK pathway reverses the therapeutic effects of BDNF and expands the shrunk lesioned area. ERK/MAPK is also involved in the beneficial effects of BDNF treatment on camptothecin-induced cortical neuronal death. VEGF has a noteworthy role in the prevention of neurodegenerative pathological condition of axotomized retinal ganglion neurons, in which ERK activation has a great impact (Jiang et al., 2009; Kilic et al., 2006). ERK also has a pivotal influence in amelioration of the global cerebral ischemia-induced cell death in hippocampal neurons, which is found that the estrogenic pathway is participating in ERK activation and the other relevant therapeutic effects (Yang et al., 2010). Activation of ERK cascade provides significant protection to the suprachiasmatic nucleus versus exposure to excessive glutamate excitotoxicity. Glutamate ensures the normal function of the CNS, although, excessive glutamate concentration can develop neurodegenerative diseases. ERK enhances the potential of neural cells against progression of neurodegeneration through the suppression of the caspase enzymes and apoptosis pathways (Karmarkar et al., 2011).