The extracellular signal-regulated kinase: Multiple substrates regulate diverse cellular functions

Abstract

The extracellular signal-regulated kinase (ERK) cascade is a central pathway that transmits signals from many extracellular agents to regulate cellular processes such as proliferation, differentiation and cell cycle progression. The signaling via the ERK cascade is mediated by sequential phosphorylation and activation of protein kinases in the different tiers of the cascade. Although the main core phosphorylation chain of the cascade includes Raf kinases, MEK1/2, ERK1/2 (ERKs) and RSKs, other alternatively spliced forms and distinct components exist in the different tiers, and participate in ERK signaling under specific conditions. These components enhance the complexity of the ERK cascade and thereby, enable the wide variety of functions that are regulated by it. Another factor that is important for the dissemination of ERKs' signals is the multiplicity of the cascade's substrates, which include transcription factors, protein kinases and phosphatases, cytoskeletal elements, regulators of apoptosis, and a variety of other signaling-related molecules. About 160 substrates have already been discovered for ERKs, and the list of these substrates, as well as the function and mechanism of activation of representative substrates, are described in the current review. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Understanding of these processes may provide a full picture of the distinct, and even opposing cellular processes that are regulated by the ERK cascade.

Regulation of normal cell cycle progression by flavin-containing oxidases

“…Additional mechanisms resulting from decreased activity of MAPK pathways (p38 MAPK and ERK1/2) (Figures 4 and 10) may have also contributed to the DPI-induced G 1 checkpoint. While the role of ERK1/2 in proliferation is well established and works downstream of many stimuli, including growth factors and hormones (Yoon and Seger, 2006), p38 MAPK has often been associated with stress responses (Dent et al, 2003); however, p38 MAPK has also been shown to promote proliferation in a variety of cell types (Juretic et al, 2001;Frigo et al, 2006). Common (for example, c-jun, c-fos) and numerous distinct substrates have been identified as targets of ERK1/2 and p38 MAPK activity (Ono and Han, 2000;Yoon and Seger, 2006).…”

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

“…It fact, nearly half of the $180 proteins thus far identified as ERKs substrates, are non-nuclear proteins. [68] The nucleo-cytoplasmic shuttling of ERKs is exquisitely regulated. Some proteins, like PEA15, prevent ERKs nuclear translocation [69] and in doing so, promote ERK cytoplasmic activities, such as the modulation of integrin receptors, [70] while interfering with ERKs nuclear functions, like the promotion of proliferation.…”

The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1

“…In particular, we investigated the impact of blocking the extracellular signal-regulated kinase (ERK1/2) MAPK signaling pathway on Mcl-1 protein expression. Although ERK1/2 MAPK have been frequently associated with cellular proliferation, their role in promoting survival in different cellular models became recently evident (Rubinfeld and Seger, 2005;Sridhar et al, 2005;Yoon and Seger, 2006). Phospho-ERK1/2 were previously shown to be overexpressed in LNCaP-IL-6 þ (Gioeli et al, 1999;Steiner et al, 2003) and Du145 prostate cancer cells (Shimada et al, 2002) and clinical specimens (Gioeli et al, 1999;Royuela et al, 2002).…”