Studies on histidine phosphorylation in Wnt/beta-catenin signaling

• Applicant: Professor Dr. Jürgen Behrens
• Subject Area: Cell Biology ; Biochemistry
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 399176750

The amino acid histidine can be modified in proteins by phosphorylation which alters the function of these protein as has been shown for a few examples in the literature. However, until now only a few studies have addressed this modification in mammalian cells. The recent generation of antibodies that specifically detect phospho-histidines in proteins now allows a more general analysis of the function of histidine phosphorylation in cellular processes. In our preliminary work we have found evidence for a role of histidine phosphorylation in the regulation of the Wnt/beta-catenin signaling pathway. This pathway takes part in numerous biological processes, including cell proliferation, stem cell development and differentiation as well as in pathological processes such as cancer. Wnt factors bind to specific cell surface receptors thereby activating cytoplasmic proteins such as Dvl2 to increase the stability of the beta-catenin protein which alters gene transcription. We found that histidine kinases and phosphatases inhibit and stimulate Wnt signaling, respectively, and that the Dvl2 protein is heavily histidine phosphorylated. The aim of our proposal is to decipher the relevance of histidine phosphorylation in Wnt signaling using molecular and cell biological methods. In particular we will focus on the consequences of histidine phosphorylation for Dvl2 activity, on the role of of the kinases and phosphatases that are part of this process, as well as the regulation of histidine phosphorylation by Wnt signaling. Moreover we will extend our analysis to detect and functionally analyze histidine phosphorylation of other key components of the pathway. Histidine phosphorylation is a relatively new research field which has to our knowledge not been applied to Wnt signaling before and hopefully will yield new clues on the function and regulation of this biologically and medically highly relevant pathway.

• DFG Programme: Research Grants