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.