Role of ERK5 in cell transformation and P53 regulation

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

The behaviour of all cells is controlled by a range of environmental factors and this is true during development in the embryo (responding to developmental signals), in the adult organism (responding to environmental changes) and in disease. Environmental changes trigger the activation of biochemical signal pathways inside the cell that act to coordinate the cellular response. These signal pathways are frequently mutated in diseases such as cancer and may represent attractive drug targets. One such signal pathway leads to the activation of an enzyme called ERK5. In this project we aim to understand how ERK5 controls processes such as cell division, cell survival and cell movement. In doing so we hope to better understand the normal function of ERK5 but also to determine if ERK5 is a good drug target in cancer.

Publications

10 25 50
 
Description We have shown that the ERK5 pathway is not required for proliferation/division or survival of diverse cell types. Rather ERK5 signalling controls cell motility and our preliminary results suggest that it may control a differentiation process called epithelial-to-mesenchymal transition. In addition we have now shown that all ERK5 kinase inhibitors that bind to the kinase domain and inhibit it also cause the paradoxical activation of the ERK5 transactivation domain through a drug-induced intramolecualr conformational change (Lochhead et al, Nat Comms 2020, in press)
Exploitation Route Our results have major implications for other academics interested in ERK5 biology but also for scientists in the pharmaceutical sector who are developing ERK5 inhibitors as drugs for various diseases. Indeed, we have initiated further collaborations in this area with both academics and industrial scientists.
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Our findings have contributed to further collaborations with a consortium of academic and industrial scientists aimed at developing ERK5 inhibitors as drugs. We have controbuted to the discovery of new class of ERK5 kinase inhibitor (Myers et al 2019 Eur J MEd Chem) and also revealed that ERK5 kinase inhibitors cause the paradoxical activation of kinase-independent functions of ERK5. These observations have important implications for ERK5 drug discovery and we are currently in discussion with a Drug Discovery SME.
First Year Of Impact 2018
Sector Education,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description BBSRC Response mode project grant
Amount £341,874 (GBP)
Funding ID BB/N015886/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2016 
End 07/2019
 
Title ERK5 KO cells lines 
Description Generated by CRISPR/Cas9; charcterisation ongoing 
Type Of Material Cell line 
Year Produced 2019 
Provided To Others? No  
Impact Too early to say 
 
Title ERK5 cell based assay 
Description A method for assessing the cellular activity of the ERK5 protein kinase 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? Yes  
Impact It has facilitated a joint academic/pharma ERK5 drug discovery project It has also facilitated academic research in this area leading to one research publication and a second in preparation 
 
Title ERK5 mutants 
Description A panel of mutants of ERK5 have been generated that are defective for ERK5 kinase inhibitor binding. These mutants no longer exhibit paradoxical activation of ERK5 transcriptional transactivation domain (TAD) by ERK5 kinase inhibitors, confirming that the TAD activating function is due to 'on target' activity of the inhibitors. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact The wider impact of this is too early to say. These tools have important implications for understanding the role of ERK5 in any and all biological responses in which ERK is implicated as they allow separation of ERK5 kinase and TAD activities. 
 
Title ERK5 WT and KO gene data set 
Description We have generated an Illumina mRNA array gene expression data set in which we have compared WT and ERK5 KO immortalised MEFs 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact The results of this work have afforded new lines of enquiry and new directions for our research and have led to further research funding applications including BB/N015886/1 It will also lead to primary research publications and the results will be of interest to collaborators in the Pharma sector 
 
Description Machine learning to inform drug discovery 
Organisation Oppilotech Ltd
Sector Private 
PI Contribution Oppilotech are a systesm biology/modelling company who employ machine learning to identify new drug targets. We have provided them with wet lab data to parameterise their models and have tested predictions arising from them
Collaborator Contribution They have performed modelling of the ERK5 pathway based on our data and information in the literature. This collaboration supported by Institute KEC funding to promote Campus Company:Institute collaborations at the Babraham Institute
Impact Too early to say but results are encouraging
Start Year 2019
 
Description Newcastle/CRT/MRC ERK5 
Organisation Newcastle University
Department Northern Institute for Cancer Research Newcastle
Country United Kingdom 
Sector Academic/University 
PI Contribution We have established a cell based assay that can be used to monitor ERK5 activity and screen for ERK5 inhibitors
Collaborator Contribution High throughput screening and follow up testing to identify ERK5 inhibitors
Impact One manuscript published; a second in preparation; further research funding application submitted; identification of ERK5 inhibitors
Start Year 2012
 
Description In conversation with the Babraham Institute - part of Cambridge Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 1:1 dialogue with general public (open invitation but registration required for numbers).
Evening reception in which we explain our science and answer questions
Part of a programme of events for the annual Cambridge Science Festival
Year(s) Of Engagement Activity 2017
 
Description Science Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Students visited the lab and undertook small lab-based proejcts supervised by students/post-docs and myself. I explained the research that we do and discussed ethical issues such as the use of animals in research.
This precipitated excellent discussion and dialogue.

We received excellent feedback from the schools involved and requests for further outreach activities
Year(s) Of Engagement Activity 2013,2014,2015,2016,2017,2018,2019,2020
 
Description Visits by Teachers 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact My lab has hosted 6th form Biology teachers who were visiting my Institution during Half Term to update their knowledge as part of their CPD
Year(s) Of Engagement Activity 2016,2017,2018,2019,2020