The impact of GRK4 on cellular signaling during cilium and kidney development

• Applicant: Professorin Dr. Melanie Philipp
• Subject Area: Pharmacology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 387683998

G protein-coupled receptor kinase 4 (GRK4) is one of seven serine-threonine kinases phosphorylating agonist-bound, actively signaling seven transmembrane receptors (also known as G protein-coupled receptors, GPCRs). GRK4 has long been assumed to have limited physiological relevance except for a very specific function in renal natriuresis. Certain genetic variants of GRK4 display elevated kinase activity and have been shown to intensify GPCR phosphorylation and their uncoupling from the signal transducing G protein. As a consequence, sodium reabsorption is increased leading to a rise in blood pressure. GRKs, however, do not only phosphorylate proteins with a GPCR architecture, but also single membrane spanning receptors and non-receptor proteins. Moreover, kinase-independent actions of GRKs have been reported, too. We have previously identified a so far unanticipated relevance of GRK4 for early kidney development and function. GRK4 appears to be a restraining factor of cilium extension suggesting a far wider reaching physiological relevance than previously acknowledged. Interestingly, this appears to be detached from its kinase activity and warrants further research into how precisely GRK4 modulates cellular signaling. With the help of unbiased screening approaches we have identified signaling networks and cellular processes linked to GRK4 function. In the next funding period we will investigate these networks in great detail and evaluate the biological relevance for cilium and kidney development using heterologous cell models and zebrafish.

• DFG Programme: Research Grants