China Scholarship Council: Disruptions to SRSF protein kinase (SRPK) signalling in human developmental disorders

The overarching goal of our research is to identify and characterise the protein kinase signalling pathways that control stem cell pluripotency and differentiation, and determine how protein kinase signalling is disrupted to cause human developmental disorders.  

Protein kinases function as reversible switches in signal transduction and as such are fundamental regulators of all cellular processes. A major role for protein kinases during human development is controlling differentiation of pluripotent stem cells (PSCs) into adult tissues, such as neurons, cardiomyocytes and hepatocytes. Furthermore, protein kinase signalling pathways are frequently dysregulated in human diseases and developmental disorders. Because protein kinase activity can be specifically and reversibly manipulated using chemical tools for therapeutics and tissue engineering, there is a pressing need to identify relevant protein kinase circuits in PSCs. However, beyond several notable examples, protein kinase pathways, regulatory mechanisms and molecular functions that control of stem cell maintenance and differentiation remain poorly understood.   

Ser-Arg Rich Splicing Factor (SRSF) Protein Kinase (SRPK) has been known for many years to phosphorylate splicing factors to promote spliceosome assembly and mRNA splicing. However, we recently showed SRPK has acquired splicing independent functions during human development. SRPK phosphorylates the E3 ubiquitin ligase RNF12/RLIM to pattern genetic programmes required for development, whilst SRPK-RNF12 pathway components are disrupted in a series of related human developmental disorders. These data suggest that SRPK plays a key role in stem cell maintenance and development, and that dysregulated SRPK signalling may underpin human developmental disorders.  

The goal of this project is to identify novel developmental SRPK substrates by state-of-the-art global phosphoprotemic profiling in PSCs. The student will explore mechanisms by which SRPK phosphorylation regulates molecular functions of key substrates, and how newly identified SRPK signalling pathways control downstream biological processes in PSCs and differentiating tissues. Finally, they will determine whether and how the SRPK signalling pathways are disrupted in patients will developmental disorders. This project offers a unique opportunity to illuminate new molecular mechanisms underpinning PSC regulation and their dysregulation in human disease.