The functions of MAPK signalling pathways in cell regulation and disease

Lead Research Organisation: MRC Protein Phosphorylation Unit

Abstract

In order for an animal to survive, its individual cells must be able to communicate with each other and respond appropriately to external factors such as changes in their environment or infection. The main way in which a cell achieves this is through the activation of intracellular signalling networks. These have many roles, but one important aspect of their function is regulating which genes are active in the cell, since changes in gene regulation are important in mediating many of the long-term effects of signalling. Deregulation of signalling networks and gene regulation frequently has adverse effects and occurs in many diseases, including cancer, neurodegeneration and inflammatory diseases such as arthritis and asthma. Compounds that selectively target these mechanisms therefore have great potential to treat these diseases. Indeed some have already been approved for use or are in clinical trials. Despite advances in this area, much is still not understood about the regulation of normal and pathological function, of the various signalling cascades in cells. Our work is focused on the functions of mitogen activated protein kinase signalling cascades, one of the signalling cascades implicated in cancer and inflammatory disease. In particular we are interested in understanding how they regulate the transcription of specific genes and how this in turn affects the function of cells in neuronal and immune systems.

Technical Summary

Mitogen activated protein kinase (MAPK) cascades are important mediators of a cells response to external signals such as mitogens and cellular stress, and are implicated in many cellular process including cell survival, proliferation, differentiation and migration. Deregulation of MAPKs is implicated in several diseases including inflammation, cancer, neurodegeneration and addiction, and drugs that target these kinases may represent a powerful way of treating these diseases. Despite this, the downstream mechanisms by which MAPKs produce the appropriate responses in cells are not well understood. We are interested in how activation of the MAPKs p38 MAPK and the MAPK-activated kinases MSK1 and MSK2, controls physiological or pathological functions in cells. While MAPK signalling is important for the correct function of many cell types and tissues, several of these kinases, including MSK1 and 2 are highly expressed in immune and neuronal cells. One reason for this may be that both cell types respond rapidly and continuously to extra-cellular signals. We are investigating the roles that MSK and p38 MAPKs play in neuronal and immune model systems using a combination of gene targeted mice, specific cell permeable inhibitors, microarrays, QPCR and proteomic techniques. We are especially interested in how MAPK signalling controls transcriptional reprogramming in neurons and immune cells, both by targeting specific transcription factors, such as CREB and ATF1, and by modifying chromatin proteins such as histone H3. We are also interested in the roles that MAPKs play in the negative regulation in the innate immune system. Finally we are also interested in the intriguing possibility that MAPK signalling may regulate the production of specific microRNAs in cells. In collaboration with others we are also looking at the effect of the gene targeting of MAPKs in models of arthritis and inflammatory bowel disease, inflammatory pain, addiction and circadian rhythms. Together, these studies should increase our understanding the physiological and pathological roles MAPK signalling in the CNS and immune systems, and identify potential targets for therapeutic intervention in these systems.

Publications

10 25 50
 
Description ARC Research Grant
Amount £170,000 (GBP)
Organisation Versus Arthritis 
Start 08/2007 
End 01/2011
 
Description Clinical PhD studentship
Amount £225,000 (GBP)
Organisation Scottish Stem Cell Network (SSCN) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 04/2013
 
Description FP6
Amount £270,000 (GBP)
Organisation Sixth Framework Programme (FP6) 
Sector Public
Country European Union (EU)
Start 01/2007 
End 09/2011
 
Description MRC Equipment Grant
Amount £90,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2009 
End 09/2009
 
Description MRC project grant
Amount £432,803 (GBP)
Funding ID MR/L000849/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2013 
End 09/2017
 
Description Project grant
Amount £202,000 (GBP)
Organisation Versus Arthritis 
Start 01/2011 
End 12/2014
 
Description project grant
Amount £203,296 (GBP)
Organisation Versus Arthritis 
Start 01/2014 
End 12/2016
 
Title gene targeted mice 
Description We have generated several novel knockout or knockin mouse lines. Phenotypic characterization of these mice is underway so their true impact is not yet known, however we have already had requests for all of these mouse lines from other labs. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2006 
Provided To Others? Yes  
Impact Several mouse lines have been provided to other research labs outside the MRC Unit, and this has resulted in new findings in the area on immunology and neurobiology that have subsequently published in international journals 
 
Description Analysis of MSK function in the CNS 
Organisation Pierre and Marie Curie University - Paris 6
Country France 
Sector Academic/University 
PI Contribution We collaborated with Dr Caboche at the Université Pierre et Marie Curie-Paris to look at the effect of MSK1 knockout in mice on the response to drugs of abuse.
Collaborator Contribution Joint publications
Impact This work resulted in two publications, one (pre 2006) in J. Neurosci. and one in J. Neurochem. (17241117)
 
Description Analysis of p38 function 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution We have helped Dr Park at the Harvard Medical School with the analysis of signalling downstream of p38 in macrophages while Dr Park has helped us with the set of of ChIP assays for cytokine promoters.
Collaborator Contribution collaborative research
Impact Two co-publications in Nature Immunology (18690222, 18677317)
Start Year 2007
 
Description Function of MSK1 in synaptic function 
Organisation University of Warwick
Department School of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We have carried out basic research related to this project and provided gene targeted mice, reagents and expertease to this project.
Collaborator Contribution Analysis of behavior and synaptic function in MSK knockout mice
Impact This collaboration has resulted in a publication (Correa et al J. Neurosci, 2012)
Start Year 2006
 
Description MAPK siganling in skin pathology 
Organisation Aarhus University
Country Denmark 
Sector Academic/University 
PI Contribution We are collaborating with Prof Iversen at the University of Aarhus to examine the effcets of some of the knockout we have generated in models of psoriasis or skin cancer.
Collaborator Contribution collaborative research
Impact This has resulted in 4 joint publications.
Start Year 2006
 
Description MSK and memory 
Organisation Baylor College of Medicine
Country United States 
Sector Hospitals 
PI Contribution We have assisted Prof Davis Sweatt by providing MSK1 knockout to look at hippocampal dependent memory.
Collaborator Contribution Joint publication
Impact Publication in J. Neurosci. (18003853)
 
Description MSK1 in neuronal development 
Organisation Ohio State University
Department Department of Neuroscience
Country United States 
Sector Academic/University 
PI Contribution Provision of gene targeted mice and reagents
Collaborator Contribution Analysis of MSK1 function in neuronal development
Impact MSK1 regulates environmental enrichment-induced hippocampal plasticity and cognitive enhancement. Karelina K, Hansen KF, Choi YS, Devries AC, Arthur JS, Obrietan K. Learn Mem. 2012 Oct 17;19(11):550-60 Mitogen- and stress-activated kinases regulate progenitor cell proliferation and neuron development in the adult dentate gyrus. Choi YS, Karelina K, Alzate-Correa D, Hoyt KR, Impey S, Simon Arthur J, Obrietan K. J Neurochem. 2012 Sep 30. doi: 10.1111/jnc.12035.
Start Year 2008
 
Description Regulation of TTP 
Organisation University of Oxford
Department Kennedy Institute of Rheumatology
Country United Kingdom 
Sector Academic/University 
PI Contribution We carried out collaborative research looking at the role of MSKs in the transcription of TTP in response to LPS.
Collaborator Contribution collaborative publication
Impact Joint publication in MCB (16845406)
 
Description Role of ERK5 in T cells 
Organisation University of Manchester
Department Faculty of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Dr Tournier in the Faculty of Life Sciences, University of Manchester provided us with conditional knockout mice for the analysis of T cell development.
Collaborator Contribution joint publication
Impact Join publication in Eurr. J. Immunol. (18792406)
 
Description Role of MSKs in response to arsenic trioxide 
Organisation Northwestern University
Department Feinberg School of Medicine
Country United States 
Sector Academic/University 
PI Contribution We assisted in the analysis of the MSKs role in response to arsenic trioxide
Collaborator Contribution Joint publication
Impact Joint publication in JBC (16403219)
 
Description Role of p38 MAPK in the heart 
Organisation King's College London
Department School of Medicine KCL
Country United Kingdom 
Sector Academic/University 
PI Contribution We are collaborating with Prof. Mike Marber at Kings College to study the role of p38 MAPK in the heart. We have provided various knockout mice for this research and currently have a co-supervised research student working on this project.
Collaborator Contribution Currently co-supervising of PhD student who is using mass spectrometry to identify new p38 substrates.
Impact To date there has been 1 joint publication form this research.
Start Year 2007
 
Description p38 delta and skin cancer 
Organisation University of Washington
Country United States 
Sector Academic/University 
PI Contribution We have provided Dr Efimova at the Washington University School of Medicine with p38detla knockout mice an p38 antibodies to run skin cancer models. This has shown that p38 delta knockout results in resistance to skin cancer.
Collaborator Contribution Joint publication
Impact Joint publication (19458068)
Start Year 2006
 
Description regulation of hDlg by p38 and ERK5 
Organisation Spanish National Research Council (CSIC)
Country European Union (EU) 
Sector Public 
PI Contribution Generation and supply of cell lines from ERK5 and p38d knockout mice
Collaborator Contribution Generation and supply of cell lines from ERK5 and p38d knockout mice
Impact Publication of 2 papers
Start Year 2008
 
Description Laboratory visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact The lab was visited by a local patient and fund raising group from Arthritis Research UK. The visit consisted of a presentation on research and tour of laboratory.

Informed public about MRC funded research.
Year(s) Of Engagement Activity 2011