The MAPK Signaling Cascades

The MAPK cascades are central signaling pathways responsive to a wide variety of extracellular cues that induce or regulate many cellular processes such as proliferation, differentiation, stress response and more. Four mammalian MAPK cascades are known at present, and those are named according to their MAPK components: extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase 1–3 (JNK), p38α-δ (p38), and ERK5. Other similar kinases have been identified as well (e.g., ERK3/4 and ERK7/8), but their distinct mode of activation suggests that they do not constitute a genuine MAPK cascade. The signals transmitted via the cascades proceed via three to five tiers of protein kinases, which phosphorylate and activate the kinases in the downstream tier, to allow a rapid phosphorylation of the cascade’s targets. Three of the tiers; MAP3K, MAPKK, MAPK, are considered the core ones, while the upstream (MAP4K) or the downstream (MAPK-activated protein kinase; MAPKAPK) tiers are not always present. Each of the tiers is composed of several components, which are either distinct gene products, or alternatively spliced isoforms that often present distinct functions. Being such central moieties in determining cell fate, the dysregulation of the cascades is involved in many pathologies such as cancer and inflammation. Therefore, these cascades serve as good targets for combating many diseases, and indeed inhibitors of the cascades have already emerged as efficient therapeutically tools in cancer. In this article we describe the components of the cascades, their function, mode of regulation, and the involvement of the cascades in diseases.