Depending upon the stimulus and cell type mitogen-activated protein kinases (MAPK) signaling pathway can transmit signals to regulate many different biological processes by virtue of their ability to target multiple effector proteins (Kyriakis JM & Avruch J 2012; Yoon and Seger 2006; Shaul YD & Seger R 2007; Arthur JS & Ley SC 2013). In particular, the extracellular signal-regulated kinases MAPK3(ERK1) and MAPK1 (ERK2) are involved in diverse cellular processes such as proliferation, differentiation, regulation of inflammatory responses, cytoskeletal remodeling, cell motility and invasion through the increase of matrix metalloproteinase production (Viala E & Pouyssegur J 2004; Hsu MC et al. 2006; Dawson CW et al.2008; Kuriakose T et al. 2014).The canonical RAF:MAP2K:MAPK1/3 cascade is stimulated by various extracellular stimuli including hormones, cytokines, growth factors, heat shock and UV irradiation triggering the GEF-mediated activation of RAS at the plasma membrane and leading to the activation of the RAF MAP3 kinases. However, many physiological and pathological stimuli have been found to activate MAPK1/3 independently of RAF and RAS (Dawson CW et al. 2008; Wang J et al. 2009; Kuriakose T et al. 2014). For example, AMP-activated protein kinase (AMPK), but not RAF1, was reported to regulate MAP2K1/2 and MAPK1/3 (MEK and ERK) activation in rat hepatoma H4IIE and human erythroleukemia K562 cells in response to autophagy stimuli (Wang J et al. 2009). Tumor progression locus 2 (TPL2, also known as MAP3K8 and COT) is another MAP3 kinase which promotes MAPK1/3 (ERK)-regulated immune responses downstream of toll-like receptors (TLR), TNF receptor and IL1beta signaling pathways (Gantke T et al. 2011).
In response to stimuli the cell surface receptors transmit signals inducing MAP3 kinases, e.g., TPL2, MEKK1, which in turn phosphorylate MAP2Ks (MEK1/2). MAP2K then phosphorylate and activate the MAPK1/3 (ERK1 and ERK2 MAPKs). Activated MAPK1/3 phosphorylate and regulate the activities of an ever growing pool of substrates that are estimated to comprise over 160 proteins (Yoon and Seger 2006). The majority of ERK substrates are nuclear proteins, but others are found in the cytoplasm and other organelles. Activated MAPK1/3 can translocate to the nucleus, where they phosphorylate and regulate various transcription factors, such as Ets family transcription factors (e.g., ELK1), ultimately leading to changes in gene expression (Zuber J et al. 2000).