MAP kinase signalling cascades and transcriptional regulation

doi:10.1016/j.gene.2012.10.033

Gene

Volume 513, Issue 1, 15 January 2013, Pages 1-13

https://doi.org/10.1016/j.gene.2012.10.033 Get rights and content

Abstract

The MAP kinase (MAPK) signalling pathways play fundamental roles in a wide range of cellular processes and are often deregulated in disease states. One major mode of action for these pathways is in controlling gene expression, in particular through regulating transcription. In this review, we discuss recent significant advances in this area. In particular we focus on the mechanisms by which MAPKs are targeted to the nucleus and chromatin, and once there, how they impact on chromatin structure and subsequent gene regulation. We also discuss how systems biology approaches have contributed to our understanding of MAPK signaling networks, and also how the MAPK pathways intersect with other regulatory pathways in the nucleus. Finally, we summarise progress in studying the physiological functions of key MAPK transcriptional targets.

Highlights

► Targeting mechanisms of MAPKs to the nucleus and chromatin ► MAPKs in controlling chromatin structure ► Systems analysis of nuclear MAPK signaling networks ► Complexities of MAPK signaling in the nucleus ► Physiological functions of MAPK transcriptional targets

Introduction

The mitogen-activated protein kinase (MAPK) family mediate cellular responses to a wide range of extracellular cues including growth factors, hormones, cytokines and stress. They are key regulators of many processes including cell growth, differentiation, cell survival, neuronal function and the immune response (Krishna and Narang, 2008). The loss of regulation of MAPK signaling is implicated in cancer and diseases affecting the immune system and the brain (Gerits et al., 2007, Wagner and Nebreda, 2009). MAPK pathways target proteins throughout the cell but many substrates are nuclear and regulate changes in gene expression. These include DNA-binding transcription factors, co-activators and co-repressors, components of chromatin modifying complexes, and histones. The phosphorylation of proteins by MAPKs can affect many aspects of their function including DNA binding, protein stability, cellular localization, and protein-protein interactions, as well as regulating other post-translational modifications (Yang et al., 2003, Whitmarsh, 2007). In addition to phosphorylating targets, there is evidence that MAPK pathway components can also function non-enzymatically to regulate transcription (Rodriguez and Crespo, 2011).

We previously reviewed the field of transcriptional regulation by MAPKs in 2003 (Yang et al., 2003), at which time a Pubmed search using the terms ‘MAP kinase’ and ‘transcription factor’ identified around 1500 publications. Currently there are over 22,000 publications on this topic thus demonstrating the expanding and continuing intense research effort to try and understand the functioning of these central signaling pathways in controlling gene expression. Previous reviews have covered how the MAPK pathways are structured, their key nuclear targets and the basic mechanisms by which the pathways control gene transcription (Yang et al., 2003, Whitmarsh, 2007, Yoon and Seger, 2006, Krishna and Narang, 2008). We now provide an update on recent advances in the field. A recent review covers the role of MAP kinases more generally in controlling gene expression in response to stress (de Nadal et al., 2011). Due to the sheer number of publications in this area, we have focused on some of the major new concepts rather than attempting to be comprehensive in our coverage of the literature. Generally, we concentrate on mammalian systems but we also discuss other key studies performed in model organisms. The main areas we discuss are; (i) a new level of understanding of how MAPKs are targeted to the nucleus and chromatin, (ii) the role of MAPKs in controlling chromatin structure, (iii) how systems biology approaches have identified new substrates and novel regulatory features of nuclear MAPK signaling networks, (iv) the complexities of intersections of other regulatory pathways with MAPK signaling in the nucleus and (v) insights into the physiological functions of key MAPK transcriptional targets.

Section snippets

The MAP kinase pathways

MAPK pathways are conserved amongst eukaryotes and feature a triple kinase module consisting of a MAPK kinase kinase (MKKK) that phosphorylates and activates a MAPK kinase (MKK) that can activate the terminal MAPK by dual phosphorylation on Thr and Tyr residues (Krishna and Narang, 2008). Upstream of the kinase module are members of the Ras and Rho families of GTPases that relay signals from receptor complexes to the module (Krishna and Narang, 2008). The components of MAPK modules associate

Nuclear localization of MAPKs

A key question is how MAPKs are directed to the nucleus in order to regulate transcription. ERK is the best studied in this regard and a number of mechanisms have been proposed (reviewed in Plotnikov et al., 2011b, Whitmarsh, 2011). It is clear that in the absence of growth stimuli the majority of ERK is anchored in the cytoplasm by associating with MEK (its upstream MKK) or with various scaffold or regulatory proteins. Upon its phosphorylation by MEK in response to mitogenic signals, ERK

The recruitment of MAPK pathway components to chromatin

Once inside the nucleus, MAPKs can phosphorylate and regulate the functions of many proteins involved in transcriptional regulation. The recently discovered substrates are listed in Table 1, and previously identified substrates are tabulated in previous reviews on this subject (Yang et al., 2003, Yoon and Seger, 2006). However, to phosphorylate their substrates, the kinases must first locate them within the complex chromatin environment. This can be achieved by a variety of mechanisms (Fig. 1),

MAP kinases and their effects on chromatin

Once recruited to the correct genomic locations, the MAPKs can then exert specific effects on transcription. Transcriptional control involves two principal stages where first the chromatin around the regulatory regions of a gene is modified and/or remodelled and secondly the recruitment and/or activity of the engaged RNA polymerase is modified. Links from MAPK signalling pathways to inducible chromatin modifications such as histone acetylation or histone H3S10 and H3S28 phosphorylation via

“Non-catalytic” functions of MAPKs

The majority of the examples of MAPK activities in the nucleus depend on the catalytic activity of their kinase domains, and hence through the direct phosphorylation of transcriptional regulators or chromatin-associated factors. However, it is becoming increasingly clear that chromatin-associated MAPKs have both kinase-dependent and kinase-independent functions. A good example of this was discussed above where ERK2 can bind directly to DNA and compete for DNA binding with the transcription

Systems level analysis of MAPK signalling to the nucleus

Until recently, studies linking cell signalling pathways to transcriptional events have been carried out on a case by case basis with binary interactions being identified between protein kinases and their direct transcriptional regulator targets. However, more recently, systems-based approaches have enabled more widespread links to be made between the MAPK cascades and transcriptional regulatory events. Connections between MAPK pathway signaling and transcriptional events have been made at

Integration of MAPK signalling with other post-translational modifications

It is becoming increasingly clear that gene regulatory responses to MAPK signalling are integrated with other cellular pathways. This is most clearly illustrated by the observation that MAPK-mediated phosphorylation of transcriptional regulators is often accompanied by additional post-translational modification events such as sumoylation, ubiquitination and acetylation (reviewed in Whitmarsh, 2007). For example, concomitant modification of transcriptional regulators can occur, or one

Physiological and pathological roles of transcription factor modification by MAPKs

A large number of MAPK substrates that regulate transcription have been uncovered (Yang et al., 2003; see Table 1) and, for many, clear affects of these phosphorylation events on gene expression have been documented. However, progress has been hindered by the difficulty of (i) convincingly demonstrating that phosphorylation sites identified in vitro are bone fide sites in cells and (ii) that a particular modification of a protein contributes to specific physiological or developmental functions

Summary and perspectives for the next decade

It is clear that the MAPK signalling cascades play an important central role in controlling cellular physiology in all eukaryotes in both healthy cells and in disease states. We now know much about how these pathways function, and in particular how they act in the nucleus to control gene expression. The last decade has seen an increase in our understanding of the molecular mechanisms through which MAPKs affect gene transcription, with marked advances in deciphering how they affect chromatin

Acknowledgments

We apologise to authors whose work is not cited here but due to the sheer volume of publications in this area, meaning that we have had to be selective with those included. The work in the author's laboratories is supported by grants from Cancer Research UK, the BBSRC, the Wellcome Trust, and a Royal Society-Wolfson award (ADS) and the Wellcome Trust and BBSRC (AJW).

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ReviewMAP kinase signalling cascades and transcriptional regulation

Abstract

Highlights

Introduction

Section snippets

The MAP kinase pathways

Nuclear localization of MAPKs

The recruitment of MAPK pathway components to chromatin

MAP kinases and their effects on chromatin

“Non-catalytic” functions of MAPKs

Systems level analysis of MAPK signalling to the nucleus

Integration of MAPK signalling with other post-translational modifications

Physiological and pathological roles of transcription factor modification by MAPKs

Summary and perspectives for the next decade

Acknowledgments

Mol. Cell

Mol. Cell. Endocrinol.

Mol. Cell

J. Biol. Chem.

Biochim. Biophys. Acta

Cell

Mol. Cell

Mol. Cell

Mol. Cell

J. Biol. Chem.

J. Mol. Biol.

J. Biol. Chem.

Cell

Dev. Biol.

J. Biol. Chem.

Cell

J. Biol. Chem.

Cell

Mol. Cell. Biol.

Cell

Curr. Biol.

Dev. Cell

Biochim. Biophys. Acta

J. Biol. Chem.

Mol. Cell

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

Two co-existing mechanisms for nuclear import of MAP kinase: passive diffusion of a monomer and active transport of a dimer

EMBO J.

c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex

Nature

PORE-ing over ERK substrates

Nat. Struct. Mol. Biol.

The hinge-helix 1 region of peroxisome proliferator-activated receptor gamma1 (PPARγ1) mediates interaction with extracellular signal-regulated kinase 5 and PPARγ1 transcriptional activation: involvement in flow-induced PPARγ activation in endothelial cells

Mol. Cell. Biol.

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Nat. Genet.

Multiple ERK substrates execute single biological processes in Caenorhabditis elegans germ-line development

Proc. Natl. Acad. Sci. U. S. A.

EGF decreases the abundance of microRNAs that restrain oncogenic transcription factors

Sci. Signal.

Amino-terminal phosphorylation of c-jun regulates stress-induced apoptosis and cellular proliferation

Nat. Genet.

MED1 phosphorylation promotes its association with mediator: implications for nuclear receptor signaling

Mol. Cell. Biol.

Elucidation of the ELK1 target gene network reveals a role in the coordinate regulation of core components of the gene regulation machinery

Genome Res.

Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells

Genes Dev.

Large-scale discovery of ERK2 substrates identifies ERK-mediated transcriptional regulation by ETV3

Sci. Signal.

Mxi2 promotes stimulus-independent ERK nuclear translocation

EMBO J.

Mxi2 sustains ERK1/2 phosphorylation in the nucleus by preventing ERK1/2 binding to phosphatases

Biochem. J.

A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program

Mol Cell.

Essential role of p18Hamlet/SRCAP-mediated histone H2A.Z chromatin incorporation in muscle differentiation

EMBO J.

Review
MAP kinase signalling cascades and transcriptional regulation