New insights into the function of the protein kinase DYRK1B, an ERK1/2 target gene

Lead Research Organisation: Babraham Institute
Department Name: Signalling

Abstract

The cells in our body are constantly subjected to changes in their environment and they contain an extensive network of signalling pathways that coordinate appropriate responses. For example, exposure to noxious chemicals will activate signal pathways that allow repair of cellular damage and promote cell survival. In the developing embryo, cells may receive stimuli or cues telling them to divide (so called growth factors) or they may receive cues telling them to cease dividing and undergo 'differentiation', a process in which cells acquire the characteristics of specialized cell types that make up the discrete tissues in our adult bodies such as nerves, blood cells or muscles.
This process of cell division and differentiation is not only important in the developing embryo but also throughout our adult lives in responding to cell and tissue damage. For example, if we tear a muscle, special 'stem cells' in the muscle start to divide and then differentiate into new muscle cells to repair muscle tissue. As we get older this process become less efficient and our capacity to repair and renew tissues is reduced. This accounts for the progressive decline in our ability to recover from injuries that pose little problem to our younger selves.
For cells to respond to growth or damage cues they must activate key growth and repair proteins; this often involves increasing the abundance of these proteins. The genetic information for these proteins is stored in discrete pieces of DNA termed genes, which reside on chromosomes in the nucleus. When a cell receives a growth or damage signal these genes are 'transcribed' into messenger RNA (mRNA) molecules, which are in turn 'translated' into the relevant proteins. This whole complex process is orchestrated by signalling pathways, which control every step. Control is the key word here. If the cells divide too much during the repair response they may become cancerous; if they do not divide enough then muscle repair may be defective.
The signalling pathways controlling cell division and differentiation typically involve cascades of enzymes called protein kinases. These enzymes 'tag' other proteins with a phosphate group (a process called phosphorylation) and this changes the activity, abundance or localisation of the protein. The tagged protein is referred to as the 'substrate' of the protein kinase enzyme. This project concerns a protein kinase called DYRK1B.
DYRK1B is one of a small family of protein kinases that are poorly understood but are believed to be very important. For example, the closely related DYRK1A may be important in Down Syndrome whilst DYRK1B itself may be a cancer-causing gene. Importantly, the abundance of DYRK1B increases substantially during the switch from cell division to cell differentiation. However we are currently ignorant about how DYRK1B controls these processes because we know very few proteins that are DYRK1B substrates (i.e. that are tagged with phosphate by DYRK1B).
We have now identified a group of proteins that are phosphorylated by DYRK1B. These proteins are involved in controlling the abundance of the mRNA molecules that are ultimately translated into growth and repair proteins. In this project we will define how DYRK1B controls these proteins, the importance of this for regulating mRNA abundance and the role that DYRK1B plays in muscle differentiation using cells that can be stimulated to change into muscle in the lab.
The results of this study should tell us more about the normal role of DYRK1B in muscle differentiation, which is important in the elderly where muscle repair can be defective. It may also be relevant in other models of differentiation where DYRK1B may be important including fat cells, which is relevant to the rise in obesity. Finally, the ability of DYRK1B to control cell division may be important in cancer. To help us maximize the impact of our research we will work with other scientists in these area.

Technical Summary

Protein kinase signalling pathways coordinate key cell fate decisions such as cell survival, proliferation, differentiation and senescence. DYRK1B is a member of the dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs), a highly conserved family of protein kinases found within the CMGC (CDK, MAPK, GSK and CLK) group of the eukaryote kinome. However, in contrast to the CDKs and MAPKs, the normal biological functions of DYRK1B (and other DYRKs) are poorly understood. DYRK1B is inducibly expressed during myogenesis and adipogenesis and upon inhibition of the ERK1/2 signalling pathway (which causes a G1 cell cycle arrest). However, few substrates of DYRK1B have been defined that might help to place it in a biological context.
We have recently collaborated with AstraZeneca in characterising a new DYRK1B-selective inhibitor, AZ191, and have used this to validate the results of a SILAC experiment to identify new DYRK1B-inducible phosphoproteins. This analysis has identified several proteins involved in mRNA degradation (e.g., Dcp1a & 1b, Edc3 & Pat1b) and translational repression (e.g. 4E-T). For two of these (Dcp1a and 4E-T) we have confirmed that they are indeed DYRK1B substrates. These proteins are all found at discrete foci within the cell called Processing Bodies (PBs); these are sites of mRNA degradation and their abundance increases upon cell stress. We find that DYRK1B co-localises with Dcp1a at processing bodies and inducible DYRK1B expression is sufficient to increase PB abundance in the absence of stress.
We suggest that DYRK1B is a novel regulator of mRNA processing. In addition, we suggest that DYRK1B is part of a signalling pathway controlling mRNA processing during ERK1/2 inhibition (G1 cell cycle arrest) and myogenesis (cell cycle arrest & differentiation). In this proposal we will test these hypotheses, anticipating that we will define a new signalling pathway controlling mRNA processing.

Planned Impact

The primary impact will come from the advancement of knowledge in mechanisms of signal transduction, related to cell responses to growth or stress cues (see Academic beneficiaries).
Impacts on industry and other stakeholders:
1. Industry: Major pharmaceutical companies (AstraZeneca, GSK, etc) remain interested in protein kinases as drug targets for a variety of diseases. The DYRKs, like RAF, MEK1/2 and ERK1/2, are readily 'druggable'. Indeed, this basic biology project developed out of a BBSRC CASE PhD with AZ with whom Cook has collaborated for ~9 years. Protein kinase inhibitors are also being used in iPS protocols in stem cell research and regenerative medicine, an area of growing commercial investment. Our research will therefore be relevant to a range of BioPharma companies contributing to UK economic competitiveness.
2. BBSRC: This research maps to Grand Challenge 3 within the BBSRC Delivery Plan: Fundamental bioscience enhancing lives and improving wellbeing. In particular: (i) basic molecular and cellular mechanisms responsible for longevity or premature ageing (e.g. triggers of cellular senescence, damage and repair processes) and (ii) basic molecular science underpinning the translation of knowledge about drug targets into chemical and biological tools and drugs. It also maps to BBSRC Strategic Priority 3: Basic Bioscience Underpinning Health. Relevant areas include: biological mechanisms of ageing and the maintenance of health; new tools in chemical biology, lipidomics and genomics; molecular cell biology, chemical biology and biochemistry to drive the discovery and validation of new drug targets or selective pharmaceuticals. Our 4sU labelling experiments fit with BBSRC's drive towards data driven science and mathematical biology and the project exemplifies the use of Partnerships, with contributions across sectors (Institutes, Universities, Industry).
3. Healthcare and 3rd sector charities: DYRK1B is expressed de novo during myogenesis, where it may promote survival, and during adipogenesis. Understanding myogenesis is important because age-related loss of muscle mass significantly impairs quality of life in the elderly. Similarly, adipocytes are critical regulators of metabolism and are involved in a variety of metabolic diseases including obesity. Sarcopenia in the elderly and obesity/diabetes are placing ever-greater demands on the NHS. Thus understanding how DYRK1B controls myogenesis (or adipogenesis) may contribute to future intervention strategies aimed at these problems. In addition, DYRK1B is expressed following ERK1/2 inhibition (a validated anti-cancer strategy) and is amplified in pancreatic and ovarian cancer (both with poor prognosis and in need of new therapeutic approaches) so our basic biology will be of interest to cancer charities as well as the healthcare professions.
Thus our research will impact through new information on drug targets (ERK1/2 pathway and DYRK1B) relevant to diseases and health deficits of old age
Training: This project will provide further training for key researchers (Ashford & Cook) in new scientific skills in growth areas (proteomics, genomics, bioinformatics). It will build on Ashford's excellent organisational skills, honed in industry, providing training for her future contribution to UK science & economic output.
Science & Society: We will continue to contribute to public STEM (science, technology, engineering and maths) understanding through our public engagement activities. Indeed, Ashford has been a STEM Ambassador throughout her PhD in the Cook lab communicating her knowledge and enthusiasm to the next generation of scientists and informing interested adults through activities such as science exhibitions and science visits to schools and local community groups.
 
Description The DYRK family of protein kinases are related to the CDKs and MAPKs; however, whilst 100s of substrates are known for the CDKs and MAPKs, relatively few DYRK substrates are known. We undertook P-SILAC MS to identify new DYRK1B inducible phosphoproteins and identified a number of proteins that are involved in mRNA decapping including Dcp1a, the regulatory subunit of the Dcp2 decapping enzyme. In common with Dcp1a, other 'hits' such 4E-T and Edc3 are found in processing bodies (PBs) sites of general mRNA decay, nonsense mediated mRNA decay, AU-rich element mediated mRNA decay and mRNA silencing. Defining the role of DYRK1B in controlling mRNA turnover would require establishing assays for monitoring Dcp1a function (Dcp1a stability, Dcp2 binding, mRNA decapping in vitro and in cells, etc) with wild type and mutant Dcp1a that lacked specific DYRK1B phosphorylation sites. Notably, DYRK1B is repressed by ERK1/2 signalling so we also wanted to understand it's regulation by ERK1/2 and its role in ERK1/2-regulated events.

Aim 1. Biochemical approaches to assess the role of DYRK1B in mRNA processing. In collaboration with AstraZeneca we completed characterisation of AZ191, a potent small molecule kinase inhibitor that selectively inhibits DYRK1B in vitro and in cells (Ref 1). This reagent has been of great use in this project.
We conducted targeted MS analysis of DYRK1B-induced Dcp1a phosphorylation in cells, using both endogenous and over-expressed Dcp1a, and in vitro. Because DYRK1B is a Pro-directed kinase (phosphorylating Ser/Thr-Pro motifs) we were able to confirm and analyse many of these sites using commercially available p-Ser/Pro or pThr-Pro antibodies from Cell Signalling Technologies. This analysis has now defined the majority of DYRK1B phosphorylation sites. Sites with most confidence are found in: (i) the N-terminal Dcp2-binding EVH1domain; (ii) adjacent to the helical leucine-rich motif that binds Edc3; (iii) the proline-rich region and (iv) the C-terminal Dcp1a trimerisation domain (four sites). Our preliminary data suggests that DYRK1B activation may increase the abundance of Dcp1 and we are exploring the underlying mechanisms. To this end we have made single and compound mutants of these sites for Dcp1a. In addition, we have validated antibodies for Dcp2 so that we can study Dcp1a-Dcp2 complexes and IP the active decapping complex. We have developed an in vitro assay which will be used to assess the effect that DYRK1B has on the rates of mRNA decapping following IP of endogenous Dcp2 or Edc3, both of which effectively precipitate the decapping complex.
At the time of writing we have recognised that this approach is limited by the unexpected complication of Dcp1b expression. It has been suggested that Dcp1b was only expressed in early embryogenesis before a switch to Dcp1a in mature tissues. However, we also found Dcp1b in our P-SILAC screen in HEK293 cells; this is a confounding factor which makes functional interrogation difficult. We will proceed to CRISPR out Dcp1b and Dcp1a individually and together to allow reconstitution experiments with our mutants.
DYRK1B regulates PB body abundance. One aim was to assess whether DYRK1B-dependent Dcp1a phosphorylation altered Dcp1a subcellular localisation. In the course of doing this we noted that activation of DYRK1B in HEK293 cells increased the number of PBs, defined by IF co-staining for Dcp1a and DDX6. Using high content imaging and Imaris software we have gone on to show that wild type DYRK1B (but not kinase dead, DYRK1Bkd) increases PB number and this is reversed by AZ191. We then extended these studies to PANC-1 cells; these cells exhibit DYRK1B amplification and have adapted to be dependent upon high levels of DYRK1B for various aspects of their biology (Ref 1). Indeed, inhibition of DYRK1B with two different DYRK1 inhibitors (AZ191 and Harmine) caused a ~70% reduction in PB number in PANC1 cells. This result was phenocopied by DYRK1B siRNA. Thus activation of DYRK1B increases PB number whereas inhibition decreases it. Thus we have identified a new function for DYRK1B - regulating the abundance of PBs, critical sub-cellular membraneless organelles where mRNA decay is controlled. This is quite a 'hot' area at the moment with several recent high profile papers studying how signalling can control phase transitions to regulate the assembly of membraneless organelles including PBs and stress granules. Thus we feel these observations are timely. New Paper planned. We are currently preparing a paper which describes our Mass Spec analysis of new DYRK1B substrates, follow up validation and the role of DYRK1B as a regulator of PB abundance.

Aim 2. Effects of DYRK1B on mRNA synthesis, stability or processing.
We have performed paired end RNA-seq with long read lengths allowing us to both define DYRK1 drive gene expression profiles but also to investigate any effects of DYRK1B on RNA processing and splicing.
Analysis of DYRK1B regulated transcripts for GO terms has revealed enrichment in genes involved in stress responses, response to amino acids (relevant to our ongoing work in BB/P007015/1), myogenesis, adipogenesis, Wnt signalling, anterior/posterior patterning, neuronal differentiation and control of cell projections. The enrichment of genes involved in myogenesis and adipogeneis is reassuring as DYRK1B has previously been implicated these processes.
We also performed an analysis of exon:intron ratios for >8,000 transcripts. The genes and corresponding transcripts selected were those which were >=1kb in length, which had at least 2 exons and which had a raw read count over the whole gene body of >=500 in all samples. This analysis revealed that samples from cells in which DYRK1B had been activated showed a statistically significant higher intronic coverage indicating larger portions of unspliced transcripts. We performed the same analysis for samples from cells in which DYRK2 had been activated; these showed a similar trend but it did not approach significance. These results require focused validation by assessing specific splicing events but they suggest that DYRKs, and specifically DYRK1B, may exert a broad influence over RNA splicing.
These data sets have generated important new insights into the biological processes that DYRK1B may regulate and will prime future papers, collaborations and lines of enquiry.

Aim 3. Define the role of DYRK1B that is induced during myogenic differentiation and upon inhibition of ERK1/2 signalling.
Because of disruptions arising from two maternity breaks we focused on (i) investigating the role of DYRK1B in cell cycle regulation and (ii) the relationship between ERK1/2 and DYRK1B
(i) The role of DYRK1B in cell cycle regulation. We used AZ191 to investigate the regulation of CCND1 (cyclin D1), a key regulator of the mammalian G1-S-phase transition. CCND1 is phosphorylated on Thr286 by GSK3ß (glycogen synthase kinase 3ß) to promote its degradation. DYRK1B has also been proposed to promote CCND1 turnover, but was reported to phosphorylate Thr288 rather than Thr286. Using in vitro kinase assays, phospho-specific immunoblot analysis and MS in conjunction with AZ191 we showed that DYRK1B phosphorylates CCND1 at Thr286, not Thr288, in vitro and in cells. In HEK293 and PANC-1 cells (which exhibit DYRK1B amplification) DYRK1B drives Thr286 phosphorylation and proteasome-dependent turnover of CCND1 and this is abolished by AZ191 or DYRK1B RNAi, but not by GSK3ß inhibitors or GSK3ß RNAi. DYRK1B expression causes a G1-phase cell-cycle arrest, but overexpression of CCND1 fails to rescue this; indeed, DYRK1B also promotes the expression of two CDK inhibitors (CDKIs), p21CIP1 and p27KIP1. These results demonstrate that DYRK1B is a novel Thr286-CCND1 kinase that acts independently of GSK3ß to promote CCND1 degradation and also acts to promote G1 arrest through expression of CDKIs. This work is now published (Ref 1), attracting citations, and set's the scene for future work on myogenic differentiation.
The related kinase, DYRK1A, is triplicated in Down Syndrome and there is growing evidence that it may be a key driver of the syndrome. Our collaborator Mariona Arbones (Instituto de Biología Molecular de Barcelona) generated mice with an extra copy of Dyrk1a and found that this lengthened the G1 phase of embryonic cortical stem (radial glia) cells, promoting asymmetric proliferative divisions at the expense of neurogenic divisions and producing a deficit in cortical projection neurons that persisted into postnatal stages. These progenitors had decreased nuclear CCND1 levels but normal CCND1 mRNA. Prompted by this we extend our studies by showing that DYRK1A also phosphorylates CCND1 at Thr286 to promotes its turnover. Thus, both DYRK1A and DYRK1B regulate CCND1 levels and in the case of triplicated DYRK1A this may contribute to defective neurogenesis in Down Syndrome. This work has now been published (Ref 2) and is already attracting citations.
(ii) The relationship between ERK1/2 signalling and DYRK1B. We found that ERK1/2 signalling repressed DYRK1B transcription so that ERK1/2 inhibition increased DYRK1B expression. We also discovered that DYRK1B underwent autophosphorylation on Ser421 in vitro and in cells and that this site contributed to DYRK1B kinase activity. Whilst a DYRK1B-S421A mutant was devoid of p-S421 in cells, DYRK1B inhibitors caused only a partial loss of p-S421 suggesting the existence of an additional kinase that could also phosphorylate DYRK1B S421. This led us to discover that ERK1/2 also phosphorylates DYRK1B at S421 in vitro and in cells. Our results show that ERK1/2 phosphorylates DYRK1B at a positive regulatory site but also represses DYRK1B expression, uncovering reciprocal regulatory inputs between two kinases involved in cell fate decisions. Finally, we have found that DYRK1B mutants that have recently been described in cancer and metabolic syndrome exhibit normal or reduced intrinsic kinase activity; in one case the mutant was virtually kinase dead. Some of these mutants are proposed to be gain-of-function mutants in biological assays so their reduced kinase activity suggests possible kinase independent or tumour suppressor functions for DYRK1B. These mutants may help in future experiments. This work has now been published (Ref 3).

Summary. Very good progress towards objectives and 3 papers published. At least two further research papers and a review are envisaged. This work has prompted talk invitations at international meetings, new international collaborations, new staff training and also primed a successful BBSRC response mode application.

Publications (Google Scholar citations) and other outputs
1. Ashford AL, Oxley D, Kettle J, Hudson K, Guichard SM, Cook SJ & Lochhead, PA. (2014) A novel DYRK1B inhibitor, AZ191, demonstrates that DYRK1B phosphorylates cyclin D1 at threonine-286, not threonine-288. Biochem J. 457: 43-56. GS 21

2. Najas S, Arranz J, Lochhead PA, Ashford AL, Oxley D, Delabar JM, Cook SJ, Barallobre MJ, Arbonés ML (2015) DYRK1A-mediated Cyclin D1 degradation in neural stem cells contributes to the neurogenic cortical defects in Down syndrome. EBioMedicine. 2: 120-134. *Highlighted in accompanying commentary. GS 23

3. Ashford AL, Dunkley TP, Cockerill M, Rowlinson RA, Baak LM*, Gallo R*, Balmanno K, Goodwin LM, Ward RA, Lochhead PA, Guichard S, Hudson K, Cook SJ (2015) Identification of DYRK1B as a substrate of ERK1/2 and characterisation of the kinase activity of DYRK1B mutants from cancer and metabolic syndrome. Cellular and Molecular Life Sciences. 73: 883-900. GS 4

4. Two further papers and a review article placing our new work in context are planned.

5. Two invited talks at the 2017 DYRK Kinase conference in St Malo, France.

6. Two summer students funded by the Erasmus Programme were hosted in the lab during this time and contributed to aspects of this work (see * in Ref 3).

7. New collaborations established with Robert Weatheritt, in the Blencowe lab at the University of Toronto. This well respected lab specialises in understanding how alternative splicing is regulated and integrated with other layers of gene expression and have helped us with analysis of splice events in our RNAseq data.

8. Interrogation of our P-SILAC data also lead to a new BBSRC grant application BB/P007015/1.

9. Both myself and the PDRA, Anne Ashford (a STEM Ambassador) and undertook several PE events during the project.
Exploitation Route Our work has demonstrated that DYRK1B phosphorylates proteins involved in post-trancriptional gene regulation. Specifically DYRK1B regulates proteins that are known to control mRNA turnover. DYRK1B also controls the abundance of processing bodies, sites of mRNA decappign and degradation.
We plan to expand this work to see if other members of the DYRK family of protein kinases serve a simialr function. Our preliminary analysis suggest that thsi is the case and we suspect that the DYRKs serve as key regulators of RNA processing, RNA stability and or translation.
Whilst there has long been academic acceptance of the importance of post-transcriptional gene regulation (RNA processing, stability, translation, etc) in many biological processes there is now a growing acceptance of its role in the progression of disease (cancer, neurodegeneration, inflammation) and a growing appetite for targeting RNA in drug discovery. Whilst direct targeting of RNA is beset with numerous challenges and will require novel and emerging chemical strategies, an alternative 'well-trodden path' is to identify druggable proteins that are involved in controlling RNA processing, stability or translation. DYRKs may represent such a class fo druggable targets so we believe our work will be of interest to the Biotech/Pharma sector in the future
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Membership of Scientific Advisory Board for Cancer Research Technology
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Scientific Advisory Board for CRUK Programme Grant awarded to Northern Institute for Cancer Research, Univeristy of Newcastle
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in a advisory committee
 
Description BBSRC Response mode project grant
Amount £327,000 (GBP)
Funding ID BB/P007015/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 06/2017 
End 05/2020
 
Title Inducible DYRK1B cells 
Description HEK293 cells lines engineered to exhibit Tet-inducible expression of the DYRK1B protein kinase 
Type Of Material Cell line 
Provided To Others? No  
Impact New knowledge of the biological function of the DYRK1B protein kinase, including new substrates. New research papers New collaborations 
 
Title Inducible DYRK2 cell line 
Description HEK293 cells lines engineered to exhibit Tet-inducible expression of the DYRK2 protein kinase 
Type Of Material Cell line 
Provided To Others? No  
Impact New knowledge of DYRK2 Identification of new substrates of DYRK2 
 
Title DYRK1B phosphoproteomics data set 
Description Using HEK293 cells exhibiting inducible expression of the DYRK1B protein kinase (HD1B cells) we have performed Phospho-SILAC mess spectrometry to identify DYRK1B-inducible phosphoproteins. Some of these turn out to be direct DYRK1B substrates 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? No  
Impact This data set has allowed us to identify new DYRK1B substrates and so has provided new insights into the function of this protein kinases in controlling gene expression and autophagy. The dataset will ultimately be released and freely available when the first mansucript is published 
 
Title DYRK1B transcriptome gene data set 
Description RNA-seq data set derived from HEK293 cells which exhibit Tet-regulated DYRK1B expression Reports genome wide changes in abundance and splicing patterns in response to DYRK1B expression 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Too soon for impacts. Data currently being analsyed 
 
Title DYRK2 Transcriptome gene data set 
Description RNA-seq data set derived from HEK293 cells which exhibit Tet-regulated DYRK2 expression Reports genome wide changes in abundance and splicing patterns in response to DYRK2 expression 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Too soon for impacts. Data currently being analysed 
 
Title DYRK2 phosphoproteomics dataset 
Description Using HEK293 cells exhibiting inducible expression of the DYRK2 protein kinase (HD2 cells) we have performed Phospho-SILAC mess spectrometry to identify DYRK2-inducible phosphoproteins. Some of these turn out to be direct DYRK2 substrates 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? No  
Impact This dataset has allowed us to identify DYRK2-inducible phosphoproteins, including new substrates, providing new insghts into the function of the DYRK2 protein in gene expression, autophagy/proteostasis and cell motility 
 
Description AZ DYRK1B 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution We have conducted research into the role and regulation of the protein kinase DYRK1B in collaboration with AstraZeneca
Collaborator Contribution AZ have provided us with reagents (kinase inhibitors, antibodies) and also performed Mass Spec analysis of samples
Impact 3 Research papers 1 Research policy paper New academic research collaborations/partnerships A new BBSRC grant supporting a post-doctoral fellow A new BBSRC PhD studentship 2 Masters student placements projects supported through the Erasmus scheme
Start Year 2009
 
Description DYRK1A developmental fates 
Organisation Molecular Biology Institute of Barcelona
Country Spain 
Sector Public 
PI Contribution DYRK1A is triplicated in Down Syndrome and evidence suggests that it may be a primary driver of this developmental disorder. We defined cyclin D1 (CCND1) as a new substrate of the protein kinase DYRK1A.
Collaborator Contribution To further our knowledge in this area we collaborated with Mariona Arbones in Barcelona who had generated a mouse model in which the DYRK1A gene is triplicated. These mice exhibit decreased nuclear levels of CCND1 in embryonic cortical stem(radial glia) cells, and that lengthens the G1 phase in these progenitors. These alterations promote asymmetric proliferative divisions at the expense of neurogenic divisions, producing a deficit in cortical projection neurons that persists in postnatal stages contributing to Downs like pathology
Impact A research paper was published in the journal EBioMedicine
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Austrian Academy of Sciences
Department Research Centre for Molecular Medicine
Country Austria 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Central European Institute of Technology (CEITEC)
Country Czech Republic 
Sector Charity/Non Profit 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Centre for Genomic Regulation (CRG)
Country Spain 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Curie Institute Paris (Institut Curie)
Country France 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation European Institute of Oncology (IEO)
Country Italy 
Sector Charity/Non Profit 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Flemish Institute for Biotechnology
Country Belgium 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Friedrich Miescher Institute for Biomedical Research (FMI)
Country Switzerland 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Helmholtz Association of German Research Centres
Department The Max Delbrück Center for Molecular Medicine (MDC)
Country Germany 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Institute for Molecular Medicine Finland
Country Finland 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Lourinhã Museum
Department Gulbenkian Institute of Science
Country Portugal 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Netherlands Cancer Institute (NKI)
Country Netherlands 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation University of Copenhagen
Department Biotech Research and Innovation Center (BRIC)
Country Denmark 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description Proteomics K Lilley 
Organisation University of Cambridge
Department Department of Biochemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution We have generated cell lines with conditional expression of various DYRK kinases (DYRK1A, DYRK1B, DYRK2, DYRK3) and are interested in using these to identify new DYRK substrates through SILAC mass spectrometry. Some of this work will be performed at the Babraham Institute but some will be conducted in collaboration with our partner Kathryn Lilley in the Cambridge Centre for Proteomics, Dept of Biochemistry
Collaborator Contribution We will prepare samples from SILAC labelled cells. Our partners will analyse on their Lumos MS Instrument and provide bioinformatics support
Impact Too early for outputs
Start Year 2015
 
Description p62 phosphorylation 
Organisation University of Dundee
Country United Kingdom 
Sector Academic/University 
PI Contribution We are examining whether the HIPK family of protein kinases can regulate p62 function by phosphorylation
Collaborator Contribution Our collaborator is studying signalling by the HIPK protein kinasses and their role in oxidaant stress responses. We are studying p62 which coordinates stress respsones to oxidative damage. Our collaboraor has approached us to expand our work to encompass the HIPKs
Impact Too early for any specific outputs or outcomes
Start Year 2018
 
Description p62 phosphorylation 
Organisation University of Tromso
Department Department of Medical Biology
Country Norway 
Sector Academic/University 
PI Contribution Sharing of data; discussion of new experimental directions; experiments We have identified p62/SQSTM1 as a novel substrate of DYRK1B and DYRK2. We are investigating the role of this phosphorylation on p62 functions in proteostasis, stress responses and nutrient signalling
Collaborator Contribution Terje Johansen's lab will share reagents and expertise and perform specific experiments to define the interaction between DYRKs and p62
Impact Too soon for any specific outputs as the collaboration has only just started. However, i have visited the University of Tromso and presented two Lectures as part of a PhD training course
Start Year 2017
 
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 Participated in Babraham Institute exhibit at Royal Society Summer Science Exhibition 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The Babraham Institute prepared an exhibit - The Ageing Clock - which exemplified aspects of our ageing research portfolio for a public audience. Tjis was selcted tp be part of the prestigious Royal Society Summer Science Exhibition and I was involved in presentign this exhbit to the Public togehter with colleagues.
Year(s) Of Engagement Activity 2018
 
Description Participation in Public Engagement event on genome editing - part of the Cambridge Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact A debate/dialgoue open to the pulbic entitled 'Genome editing: How far should we go'
Year(s) Of Engagement Activity 2018
 
Description School visits 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The students were enthused about the topic of my presentation and this led to dialogue and discussion about several issues including new cancer therapies, evolution of drug resistance in cancer, the use of animals in research.


Anecdotally, the institute received requests for summer placement students following this visit.
Year(s) Of Engagement Activity 2014,2015,2016,2017,2018
 
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 Regional
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
 
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 I hosted two 6th form Biology teachers (one PhD trained, the other MSc trained) who were visiting my Institution during Half Term to update their knowledge as part of their CPD
Year(s) Of Engagement Activity 2016