Abstract
The RAF/MEK/ERK signaling pathway regulates diverse cellular processes as exemplified by cell proliferation, differentiation, motility, and survival. Activation of ERK1/2 generally promotes cell proliferation, and its deregulated activity is a hallmark of many cancers. Therefore, components and regulators of the ERK pathway are considered potential therapeutic targets for cancer, and inhibitors of this pathway, including some MEK and BRAF inhibitors, are already being used in the clinic. Notably, ERK1/2 kinases also have pro-apoptotic functions under certain conditions and enhanced ERK1/2 signaling can cause tumor cell death. Although the repertoire of the compounds which mediate ERK activation and apoptosis is expanding, and various anti-cancer compounds induce ERK activation while exerting their anti-proliferative effects, the mechanisms underlying ERK1/2-mediated cell death are still vague. Recent studies highlight the importance of dual-specificity phosphatases (DUSPs) in determining the pro- versus anti-apoptotic function of ERK in cancer. In this review, we will summarize the recent major findings in understanding the role of ERK in apoptosis, focusing on the major compounds mediating ERK-dependent apoptosis. Studies that further define the molecular targets of these compounds relevant to cell death will be essential to harnessing these compounds for developing effective cancer treatments.
Highlights
The MAPK signaling pathway, comprised of RAS, RAF, MEK, and ERK is an evolutionarily conserved signaling cascade that plays a fundamental role in the control of key cellular processes, including cell survival and proliferation
Growing literature, as shown in this review, indicates that the ERK signaling pathway mediates apoptosis induced by various stimuli in different settings
ROS can stimulate ERK signaling via activation of upstream activators and inactivation of catalytic activity of dual-specificity phosphatases (DUSPs), which leads to sustained ERK activation due to the lack of negative feedback responses elicited by DUSPs
Summary
The MAPK signaling pathway, comprised of RAS, RAF, MEK, and ERK is an evolutionarily conserved signaling cascade that plays a fundamental role in the control of key cellular processes, including cell survival and proliferation. The RAS/RAF/MEK/ERK pathway (hereinafter referred to as the ERK cascade) is a highly conserved signaling mechanism, which is used to connect extracellular signals from cell surface receptors to machinery that regulates multiple critical physiological processes, including growth, proliferation, differentiation, migration, and apoptosis (Figure 1) [28]. DUSP6 protein expression correlates with ERK signaling activation in lung cancer cell lines, and regulation of DUSP6 is mediated at the promoter level by the ETS1 transcription factor, a well-known nuclear target of activated ERK. Another example of the negative feedback regulation of ERK signaling includes direct negative regulation of upstream kinases of the ERK signaling cascade by ERK phosphorylation. In contrast to ERK activation, manipulation to dampen ERK1/2 signaling in response to these stimuli promotes apoptosis
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