TRAF ubiquitin ligases

Mitogen-activated protein kinase (MAPK) pathways are important regulators of cellular responses to many extracellular stimuli. Typically, eukaryotic cells have several parallel MAPK pathways, which allow the integration of signals from different stimuli. One of these, the p38 MAPK pathway, has been conserved from yeast to mammals, in which there are four family members: p38a (MAPK14), p38b (MAPK11), p38d (MAPK13), and p38g (MAPK12). Most of what has been published on p38 MAPK signaling refers to p38a, which is ubiquitously expressed at high levels in most cell types. In contrast, p38b seems to be normally expressed at lower levels. The other two family members have more restricted tis-sue expression patterns. Activation of p38a is induced by most stress stimuli, including UV light, oxidative stress, and heat or osmotic shock, but also when cells are exposed to cytokines, chemokines, hormones, or growth factors. Taken together, it appears that p38a signaling helps cells to adequately respond to changing environmental conditions.The extracellular stimuli usually lead to the activation of MAPKs via a cascade of phosphorylation events that involves at least two other kinases acting sequentially. MAP2Ks directly phosphorylate the activation loop of p38a on Thr and Tyr residues, leading to a conformational change that results in kinase activation. The three MAP2Ks that are known to activate p38a are, in turn, activated by phosphorylation on two conserved residues catalyzed by ten MAP3Ks. Upstream in the pathway, there is more diversity, and the acti-vation of different MAP3Ks involves mechanisms like phosphorylation, ubiquitination, or protein-protein interaction, which facilitate integration of a wide range of signals. There is also evidence for the activation of p38a in particular cases by a noncanonical mechanism based on autophosphorylation, independently of MAP2Ks. Once p38a becomes activated, it can phosphorylate many substrates on Ser or Thr residues. This schematic depicts upstream regulators leading to p38a activation and the myriad downstream targets of p38a.