Cancer Letters

Cancer Letters

Volume 384, 1 January 2017, Pages 19-26
Cancer Letters

Mini-review
Targeting p38 MAP kinase signaling in cancer through post-translational modifications

https://doi.org/10.1016/j.canlet.2016.10.008Get rights and content

Highlights

  • p38 MAPK signaling is a major organizer of cellular response to external stimuli.

  • Accumulating evidence suggests a dual role of p38 MAPK signaling in cancer.

  • More PTMs in the p38 signaling landscape are being increasingly unveiled.

  • Deeper insights into PTMs and their impact on p38 signaling in cancer are needed.

Abstract

The p38 MAPK signaling pathway is a key signal transduction cascade that cancer cells employ to sense and adapt to a plethora of environmental stimuli, and has attracted much attention as a promising target for cancer therapy. Accumulating evidence suggests a dual role of p38 signaling in various types of cancers, wherein the p38 pathway can both suppress and promote tumor growth, metastasis and chemoresistance. This dual role of p38 signaling, along with its context dependence and versatility, poses a great challenge for developing efficient anticancer treatment. An increasing number of studies showed that p38 signaling is subject to regulation by a variety of post-translational modifications (PTMs). Recently, large-scale proteomics profilings have identified a large number of PTMs on key components of the p38 pathway. However, the majority of these modifications and their biological significance in cancer remain uncharacterized. In this review, we highlight a series of studies that focus on the PTMs in the p38 cascade landscape, and discuss the complexity and implications of these PTMs in p38 MAPK signaling regulation.

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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