Mini-reviewTargeting p38 MAP kinase signaling in cancer through post-translational modifications
Section snippets
A dual role of p38 MAP kinase signaling in cancer
The p38 mitogen-activated protein kinase (MAPK) pathway is a signal transduction pathway that plays key roles in cellular adaptation to external stimuli. Since the identification of p38α, research over the past two decades has established roles of p38 signaling in stress response and inflammation. p38 MAPK activation has been shown to mediate cellular responses to UV irradiation, osmotic shock, ischemia, DNA damage, and growth factors [1], [2], [3].
In addition to stress response and
p38 MAPK activation by phosphorylation
Like many other signaling modules, p38 signaling is driven by a common, well-characterized type of PTM: phosphorylation (Table 1). So far three activation mechanisms have been described for p38 signaling: the canonical MAPK signaling module, TAB1-mediated p38α autoactivation, and TCR-mediated p38α/β autoactivation. These mechanisms culminate in p38 MAPK activation through phosphorylating threonine and/or tyrosine residues in the activation loop [1], [13]. These phosphorylations induce
Regulation of p38 MAPK signaling through other types of PTMs
Besides phosphorylation, a number of additional types of PTMs have been identified and characterized on numerous components within the p38 signaling landscape (Table 1). There is a large body of evidence illustrating various mechanisms by which PTMs regulate not only protein level and turnover, but also its interactome, subcellular distribution, activity, and substrate specificity. Phosphorylation so far has been the most successful target PTM for developing pharmacological interventions for
Concluding remarks
The p38 MAPK signaling pathway functions as a major orchestrator of cellular responses to a variety of extracellular stimuli. In response to adverse signals, the p38 cascade determines cell fate in cooperation with other pivotal signaling cascades. The majority of existing evidence suggests a dual role of p38 signaling in various types of cancers, wherein the p38 pathway suppresses tumorigenesis or promotes tumor growth, metastasis and chemoresistance. Moreover, the evidence also suggests
Acknowledgements
This work was supported by Marie-Curie CIG (#612816) and Israel Cancer Association (ICA) grants (#20160073) awarded to MB. It was also supported by Dayan Family Foundation, Dorothy and Harold Greenwald Foundation, and by the Harry B. Helmsley Charitable Trust.
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