The ERK1/2 pathway of mammals is probably the best-characterized MAPK system. The most important upstream activators of this pathway are the Raf proteins (A-Raf, B-Raf or c-Raf), the key mediators of response to growth factors (EGF, FGF, PDGF, etc.); but other MAP3Ks such as c-Mos and Tpl2/Cot can also play the same role. All these enzymes phosphorylate and thus activate the MKK1 and/or MKK2 kinases, that are highly specific activators for ERK1 and ERK2. The latter phosphorylate a number of substrates important for cell proliferation, cell cycle progression, cell division and differentiation (RSK kinases, Elk-1 transcription factor, etc.)
In contrast to the relatively well-insulated ERK1/2 pathway, mammalian p38 and JNK kinases have most of their activators shared at the MAP3K level (MEKK1, MEKK4, ASK1, TAK1, MLK3, TAOK1, etc.). In addition, some MAP2K enzymes may activate both p38 and JNK (MKK4), while others are more specific for either JNK (MKK7) or p38 (MKK3 and MKK6). Due to these interlocks, there are very few if any stimuli that can elicit JNK activation without simultaneously activating p38 or reversed. Both JNK and p38 signaling pathways are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in adaptation to stress, apoptosis or cell differentiation. JNKs have a number of dedicated substrates that only they can phosphorylate (c-Jun, NFAT4, etc.), while p38s also have some unique targets (e.g. the MAPKAP kinases MK2 and MK3), ensuring the need for both in order to respond to stressful stimuli.
ERK5 is part of a fairly well-separated pathway in mammals. Its sole specific upstream activator MKK5 is turned on in response to the MAP3 kinases MEKK2 and MEKK3. The specificity of these interactions are provided by the unique architecture of MKK5 and MEKK2/3, both containing N-terminal PB1 domains, enabling direct heterodimerisation with each other. The PB1 domain of MKK5 also contributes to the ERK5-MKK5 interaction: it provides a special interface (in addition to the D-motif found in MKK5) through which MKK5 can specifically recognize its substrate ERK5. Although the molecular-level details are poorly known, MEKK2 and MEKK3 respond to certain developmental cues to direct endothel formation and cardiac morphogenesis. While also implicated in brain development, the embryonic lethality of ERK5 inactivation due to cardiac abnormalities underlines its central role in mammalian vasculogenesis. It is notable, that conditional knockout of ERK5 in adult animals is also lethal, due to the widespread disruption of endothelial barriers. Mutations in the upstream components of the ERK5 pathway (the CCM complex) are thought to underlie cerebral cavernous malformations in humans.