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

双特异性酪氨酸磷酸化调节激酶（DYRKs）是与MAP激酶（例如ERK）相关的五种蛋白激酶家族。DYRKs在正常发育和体内平衡中似乎是重要的，并且在某些疾病（唐斯综合征、癌症）中可能是失调的，但它们的确切功能仍然是谜。基于我们在MAPK生物学方面的成功（1），我们对DYRKs及其在控制细胞周期、存活、分化和自噬中的作用越来越感兴趣。然而，很少DYRK底物或DYRK靶基因已被定义来解释这些酶如何调节这样的细胞命运decisions.We现在已经建立了一个面板的细胞系，表现出Tet-regulated不同DYRK蛋白激酶的表达。此外，我们还有一组细胞，其中单个DYRK已被CRISPR/Cas9技术敲除，并可获得独特的专有DYRK抑制剂。我们正在使用这个“DYRK工具包”来研究DYRK激活/失活的细胞后果，并应用转录组学/磷酸蛋白质组学方法来了解DYRKs的生物学功能。例如，我们已经使用该资源来显示DYRK 1B和DYRK 1A磷酸化细胞周期蛋白D1以控制细胞周期的G1期，并且最近使用质谱法来鉴定和验证全新的DYRK 1B底物（未发表的观察结果）。在这个项目中，学生将使用“DYRK工具包”来研究个别DYRK如何影响细胞周期，细胞存活和自噬，包括新DYRK底物的鉴定。该项目将产生和整合基因组学和蛋白质组学数据，以确定DYRK蛋白激酶的生物学功能。

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of the cell cycle and have used recently mass spectrometry to identify and validate completely new DYRK1B substrates (unpublished observations).In this project the student will use the 'DYRK toolkit' to investigate how individual DYRKs influence cell cycle, cell survival and autophagy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.