Mitogen-activated protein kinase (MAPK) cascades are among the most intensively studied
signal transduction systems. MAPK pathways are evolutionarily conserved in all eukaryotes
and allow cells to respond to changes in the physical and chemical properties of the
environment and to produce an appropriate response by altering many cellular functions
including cell differentiation, cell death, proliferation, metabolism rate, or the
interaction with other cells. Four subfamilies of MAPKs have been extensively characterized
in mammalian cells: ERK1/2, JNKs, p38s and ERK5 (Schaeffer and Weber, 1999; Cuenda
and Rousseau, 2007; Gaestel et al., 2009; Kyriakis and Avruch, 2012; Arthur and Ley,
2013). All MAPK cascades comprise several molecular intermediaries at sequential level,
which become activated in response to a broad panel of intra- and extra-cellular stimuli.
They are typically organized in a three-kinase architecture consisting of a MAPK,
a MAPK activator (MEK, MKK, or MAPK kinase), and a MEK activator [MEK kinase (MEKK)].
Transmission of signals is normally achieved by sequential phosphorylation and activation
of the components specific to a respective cascade (Schaeffer and Weber, 1999; Kyriakis
and Avruch, 2012).
In the past decade, there has been a vast increase of new works using different approaches
and technologies that have provided valuable insight into the spatiotemporal dynamics,
the regulation and functions of MAPK pathways, as well as their therapeutic potential.
Since MAPK research is a very dynamic field, our aim planning this topic was to generate
an opportunity in which MAPK researchers could make public their latest discoveries
and also review and revisit different aspects of this research area.
Several key issues in the MAPK field are discussed in this topic. One of them is how
selectivity and efficiency of MAPK pathways is preserved, despite the apparent ability
of their components to function in multiple pathways. Particularly, Casar and Crespo
describe recent findings on the ERK1/2 scaffold proteins, which maintain pathway integrity
and signaling efficiency. Scaffold proteins connect different MAPK pathway elements
into multi-enzymatic complexes (Kyriakis and Avruch, 2012), which fine-tune signal
amplitude and duration, and provide signal fidelity by isolating these complexes from
external interferences. Also, scaffold proteins are spatial regulators of MAPK signals,
and depending on the subcellular localization from which the activating signals arise,
defined scaffolds determine which substrates are phosphorylated. In this respect,
Gaestel describes how the MAPKs ERK1/2 and p38 signal further downstream by the activation
of the so-called MAPK-activated protein kinases (MAPKAPKs). He summarizes recent findings
regarding the molecular basis of signaling complexes between MAPKs and MAPKAPKs and
describes the non-canonical activation of the ERK1/2 substrate RSKs by p38-MK2/3 in
dendritic cells. In his mini-review Gaestel also discusses recent challenges arising
from off target effects of the widely used RSK inhibitors SL0101 and BI-D1870.
Functional redundancy between MAPKs is very common since there are more than one isoform
at each level of the MAPK cascades. This issue is also discusses in the topic. Buscà
et al. and Saba-El-Leil et al. focus their attention on ERK1 and ERK2. Buscà et al.
collect data on ERK1 vs. ERK2 gene structures, protein sequences, expression levels,
structural and molecular mechanisms of activation and substrate recognition, and very
nicely perform a rigorous analysis of studies regarding the individual roles of ERK1
and ERK2. They conclude that ERK1 and ERK2 exhibit functional redundancy and propose
the concept of the global ERK quantity as being the essential determinant to achieve
ERK function. Saba-El-Leil et al. also point out evidence supporting the ERK1 and
ERK2 redundant roles in embryonic development and in physiology, and in addition discuss
the redundancy of JNK (JNK1/2/3) and p38 (p38α/β/γ/δ) isoforms.
Additionally, this topic includes some latest advances on MAPK function and implication
in differentiation, inflammation and cancer. Two reviews focus on p38MAPK signaling
in cell differentiation; particularly, Segalés et al. nicely summarize the molecular
mechanisms implicated in the transition of muscle satellite cells throughout the distinct
myogenic stages and also discuss recent findings on the causes underlying satellite
cell functional decline with aging. They describe the important function of p38 in
myogenesis, and in building up satellite cell adaptive responses in muscle regeneration;
and discuss how these responses are altered in aging. On the other hand, Rodríguez-Carballo
et al., discuss the role of MAPKs—centring on p38—on the regulation of transcription
factors that are essential for adipocyte, chondrocytes, osteoblasts and osteoclasts
differentiation and function. They also describe how inflammatory cytokines activate
MAPKs during the differentiation process. It is well established that MAPKs are not
only activated in response to inflammatory cytokines, but also serve as key regulators
of pro-inflammatory cytokines biosynthesis, which makes different components of these
pathways potential targets for the treatment of autoimmune and inflammatory diseases
(Cuenda and Rousseau, 2007; Gaestel et al., 2009; Arthur and Ley, 2013). Lloberas
et al., describe how the MAPK phosphatase MKP-1 is regulated, and also explain the
balancing role of MKP-1 in the control of macrophage behavior by dephosphorylating
MAPKs, which in turn have a strong impact in the inflammatory response since macrophages
represent the primary host response to pathogen infection and link the immediate innate
defense to the adaptive immune system. Reyskens and Arthur, review the last findings
on MSK1/2, which are common p38 and ERK1/2 substrates. MSK1/2 are nuclear proteins
that phosphorylate multiple substrates, including CREB or Histone H3, and are highly
expressed in immune and nervous systems. The anti-inflammatory role of MSKs, by regulating
the production of IL-10, and their implication in neuronal proliferation and synaptic
plasticity in the central nervous system are described in this review. In addition,
Richter et al. present their last data on the analysis of protein kinases during macrophage
differentiation by using kinomics and phosphoproteomics in the human monocytic cell
line THP-1. They find that monocyte-to-macrophage differentiation is associated with
major rewiring of MAPK signaling networks and demonstrate that protein kinase MAP3K7
(TAK1) is critical for bacterial killing, chemokine production and differentiation.
Other process in which MAPKs are central elements is cancer development (Wagner and
Nebreda, 2009; Dorard et al., 2017). Rousseau and Martel report an analysis of non-synonymous
somatic mutations found in the TLR signaling network in lymphoid neoplasms. Lymphoid
neoplasms form a family of cancers affecting B-cells, T-cells, and NK cells. The authors'
findings suggest that TLR-mediated ERK1/2 activation via TPL2 is a novel path to tumorigenesis,
and they propose that inhibition of ERK1/2 activation would prevent tumor growth in
hematologic malignancies such as Waldenstrom's Macroglobulinemia, where the majority
of the cells carry the MYD88[L265P] mutation. In the skin cancer context, Wellbrock
and Arozarena review the complexity of the ERK signaling pathway in melanocytes, the
healthy pigment cells that give rise to melanoma. They also discuss the mechanisms
of action of different ERK-pathway inhibitors and their correlation with clinical
response, the mechanisms of drug-resistance that limit patient's response, and new
therapeutic opportunities for melanoma treatment targeting the ERK pathway. During
the last decade members of the p38 signaling pathway have joined the group of canonical
signaling pathways involved in tumor development and therefore are potential target
for cancer treatment (Cuenda and Rousseau, 2007; Wagner and Nebreda, 2009). To this
respect, García-Cano et al. summarize the role of p38MAPK in chemotherapy as well
as the advantages that p38MAPK inhibition can bring to cancer therapy. The authors
conclude that targeting p38MAPK for cancer treatment could be a double-edged sword
depending on the patient's pathology and treatment.
Finally, two contributions, which shape the final outcome of the topic, address different
aspects the some of the less studied MAPKs: ERK5, p38γ and p38δ. Gomez et al., review
the role of ERK5 in regulating cell proliferation by mechanisms that are both dependent
and independent of its kinase activity. They summarize the last findings regarding
the complex regulation of ERK5 by upstream kinases and stabilizing chaperones in normal
and cancer cells, and also during cell cycle. The authors describe the different mechanisms
involved in the nuclear translocation of ERK5, -where mediates gene transcription-
and discuss the possibility of targeting ERK5 to tackle different types of cancer.
Escós et al. give a general overview of the recent advances made in defining the functions
of the alternative p38, p38γ and p38δ, focusing in innate immunity and inflammation.
They also discuss the potential of the pharmacological targeting of p38γ and p38δ
pathways to treat autoimmune and inflammatory diseases, as well as cancer linked to
We hope that all the information compiled in this eBook will be useful to researchers
in this exciting field, and stimulate them to continue in their efforts to increase
our knowledge on MAPK cascades. We want to acknowledge the great work of the authors,
co-authors, and reviewers, and to thanks the superb support received from Frontiers
Team members at all times.
All authors listed have made a substantial, direct and intellectual contribution to
the work, and approved it for publication.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.