Mitogen-activated protein kinases (MAPKs) are a widely conserved family of serine/threonine protein kinases involved in many cellular programs such as cell proliferation, differentiation, motility, and death. The ERK1/2 (p44/42) signaling pathway can be activated in response to a diverse range of extracellular stimuli including mitogens, growth factors, and cytokines. Upon stimulation, a sequential three-part protein kinase cascade is initiated, consisting of a MAP kinase kinase kinase (MAPKKK), a MAP kinase kinase (MAPKK), and a MAP kinase (MAPK). Multiple ERK1/2 MAPKKKs have been identified, including members of the Raf family as well as Mos and Tpl2/Cot. MEK1 and MEK2 are the primary MAPKKs in this pathway. MEK1 and MEK2 activate ERK1 and ERK2 through phosphorylation of activation loop residues Thr-202/Tyr-204 and Thr-185/Tyr-187, respectively. ERK1/2 are negatively regulated by a family of dual-specificity (Thr/Tyr) MAPK phosphatases. Several downstream targets of ERK1/2 have been identified, including p90RSK and the transcription factor Elk-1.
