Structural and functional analysis of WNT receptors : with emphasis on FZD6

Many cellular processes are dependent on the activation of G protein-coupled receptors (GPCRs). The development of drugs that can specifically target GPCRs and their corresponding signalling cascades is of high interest. Today, almost 1000 different GPCRs are known and even though about 40 % of all prescribed pharmaceuticals on the market target GPCRs either directly or indirectly, only a small fraction of receptors are druggable.

One specific Class of GPCRs are Frizzled (FZD), which belong to the Class F of GPCRs. Nineteen mammalian WNTs can bind to 10 FZDs in various combinations resulting in the activation of different downstream pathways such as WNT/β-catenin, WNT/planar cell polarity and WNT/Ca2+. These signaling pathways are highly involved in cell polarity, embryonic development, formation of neural synapses, cell proliferation, differentiation and many other processes in developing and adult organisms. Mutations and/or misregulation within the pathways are linked to many diseases ranging from cancer, inflammatory diseases to metabolic and neurological disorders. Therefore, targeting WNT receptors pharmacologically would be advantageous. Currently very little is known in regard to structure and precise function of Class Frizzled receptors. Particular the link between FZDs and heterotrimeric G proteins is a matter of discussion in the field. Furthermore, the lack of high throughput screening assays hampers the development of small compounds targeting FZDs.

This thesis provides advanced insight into structural and functional aspects of WNT receptors with the focus on FZD6, from which not only future research but also drug discovery could benefit from. In addition, this thesis intends to provide novel tools to study this unconventinal class of receptors, which will allow extending the knowledge to the entire Class F and possible to other GPCRs.

List of scientific papers

I. Disheveled regulates precoupling of heterotrimeric G proteins to Frizzled 6. Kilander MB, Petersen J, Andressen KW, Ganji RS, Levy FO, Schuster J, Dahl N, Bryja V, Schulte G FASEB J. 2014 May;28(5):2293-305
https://doi.org/10.1096/fj.13-246363

II. Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling Julian Petersen, Shane Wright, David Rodríguez, Noa Lahav, Aviv Vromen, Johan Strömqvist, Stefan Wennmalm, Assaf Friedler, Jens Carlsson and Gunnar Schulte [Manuscript]

III. Identification of a molecular switch in TM6/7 in Frizzled 6 regulating receptor activation Julian Petersen, Belma Hot, Kateřina Straková, Jana Valnohová, Evgeny Ivashkin, Maria Consuelo Alonso Canizal, Carsten Hoffmann, Igor Adameyko, Vita Bryja, David Rodríguez, Jens Carlsson and Gunnar Schulte [Manuscript]

IV. Asymmetry of VANGL2 in migrating lymphocytes as a tool to monitor activity of the mammalian WNT/planar cell polarity pathway Markéta Kaucká, Julian Petersen, Pavlína Janovská, Tomasz Radaszkiewicz, Lucie Smyčková, Avais M Daulat, Jean-Paul Borg, Gunnar Schulte, Vitezslav Bryja Cell Communication and Signaling (2015) 13:2
https://doi.org/10.1186/s12964-014-0079-1