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Molecular basis of p38a MAPK signaling
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[eng] Cells often need to respond to damaging internal and external stimuli. One of the pathways that is frequently activated by stress stimuli involves activation of the kinase p38alpha, which can phosphorylate different substrates, including MK2. Experiments using purified proteins have shown that non-phosphorylated p38alpha and MK2 can form a tight complex, in which structural constraints impede the interaction of both kinases with effectors and regulators. It is therefore critical to understand how the interaction between p38alpha and MK2 is regulated to ensure that they can release from each other and phosphorylate the required substrates that mediate their functions. Here, we show that in cells under homeostatic conditions, endogenous p38alpha and MK2 form a stable complex that is disrupted upon phosphorylation of both proteins. The separation of the two kinases causes MK2 destabilization and degradation by the proteasome in a MDM2-dependent manner. Depending on the intensity of the stimuli, p38alpha and MK2 undergo different fates. Transient stimulation leads to complex separation and MK2 degradation followed by increased MK2 expression, and the eventual reassembly of the p38alpha:MK2 complex. On the contrary, in cells exposed to strong stimuli that lead to sustained p38alpha activation, as it is often the case with stress, both kinases remain phosphorylated, cannot bind to each other and eventually become destabilized, being unable to recover the steady state. Taken together, our results illustrate a new mechanism of p38alpha signaling regulation based on the p38alpha:MK2 complex dynamics, which may have implications for different processes regulated by p38alpha and MK2 signaling.
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GUTIERREZ PRAT, Núria. Molecular basis of p38a MAPK signaling. [consulta: 7 de febrer de 2026]. [Disponible a: https://hdl.handle.net/2445/125684]