Cell fate signalling by the DYRK protein kinases, relatives of the MAP kinases

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The dual-specificity tyrosine-phosphorylation-regulated kinases (DYRKs) are a family of five protein kinases related to the MAP kinases (e.g. ERK). The DYRKs appear to be important in normal development and homeostasis and may be de-regulated in certain diseases (Downs Syndrome, Cancer) but their precise functions remain enigmatic. Based on our success in MAPK biology (1) we are increasingly interested in the DYRKs and their role in control of cell cycle, survival, differentiation and autophagy. However, few DYRK substrates or DYRK target genes have been defined to explain how these enzymes regulate such cell fate decisions.We have now established a panel of cell lines that exhibit Tet-regulated expression of the different DYRK protein kinases. In addition we have a panel of cells in which the individual DYRKs have been knocked out by CRISPR/Cas9 technology and have access to unique, proprietary DYRK inhibitors. We are using this 'DYRK toolkit' to investigate the cellular consequences of DYRK activation/inactivation and to apply transcriptomics/phosphoproteomics approaches to understand the biological functions of the DYRKs. For example, we have used this resource to show that DYRK1B and DYRK1A phosphorylate cyclin D1 to control the G1 phase of the cell cycle and have used recently mass spectrometry to identify and validate completely new DYRK1B substrates (unpublished observations).In this project the student will use the 'DYRK toolkit' to investigate how individual DYRKs influence cell cycle, cell survival and autophagy including the identification of new DYRK substrates. The project will generate and integrate genomic and proteomics data to define the biological functions of the DYRK protein kinases.