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Employing Genetically Encoded, Biophysical Sensors to Understand WNT/Frizzled Interaction and Receptor Complex Activation

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Pharmacology of the WNT Signaling System

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 269))

Abstract

The Frizzled (FZD) family of WNT receptors consists of ten paralogues in mammals. They belong to the superfamily of G protein-coupled receptors and regulate crucial processes during embryonic development. Dysregulated FZD signaling leads to disease, most prominently to diverse forms of cancer, which renders these receptors attractive for drug discovery. Recent advances in assay development and the design of genetically encoded biosensors monitoring ligand–receptor interaction, conformational dynamics, and protein–protein interaction have allowed for a better pharmacological understanding of WNT/FZD signal transduction and open novel avenues for mechanism-based drug discovery and screening. In this chapter, we summarize the recent progress in the molecular dissection of FZD activation based on advanced biosensors.

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Abbreviations

BRET:

Bioluminescence resonance energy transfer

cpGFP:

Circularly permuted green fluorescent protein

DVL:

Disheveled

FlAsH:

Fluorescein arsenical hairpin binder

FRAP:

Fluorescence recovery after photobleaching

FRET:

Förster resonance energy transfer

FZD:

Frizzled

GPCR:

G protein-coupled receptor

HTS:

High throughput screening

Nluc:

Nanoluciferase

WNT:

Wingless/Int1 proteins

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Acknowledgements

The work in the Schulte laboratory was supported by grants from Karolinska Institutet, the Swedish Research Council (2015-02899; 2019-01190), the Swedish Cancer Society (CAN2017/561, 20 1102 PjF, 20 0264 P), the Novo Nordisk Foundation (NNF17OC0026940, NNF20OC0063168), The Lars Hierta Memorial Foundation (FO2019-0086, FO2020-0304), The Alex and Eva Wallström Foundation (2020-00228), The Swedish Society of Medical Research (SSMF; P19-0055), and the German Research Foundation (DFG; 427840891). Computational resources were provided by the Swedish National Infrastructure for Computing – National Supercomputer Centre (NSC) in Linköping and KTH Royal Institute of Technology (PDC) in Stockholm (SNIC 2020/5-500).

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  1. Section for Receptor Biology and Signaling, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

    Pawel Kozielewicz, Hannes Schihada & Gunnar Schulte

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  1. Pawel Kozielewicz
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  2. Hannes Schihada
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  3. Gunnar Schulte
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Correspondence to Gunnar Schulte .

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  1. Department of Physiology & Pharmacology Section for Receptor Biology & Signaling, Karolinska Institutet Biomedicum 6D, Stockholm, Sweden

    Gunnar Schulte

  2. Department of Physiology & Pharmacology Section for Receptor Biology & Signaling, Karolinska Institutet Biomedicum 6D, Stockholm, Sweden

    Pawel Kozielewicz

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Kozielewicz, P., Schihada, H., Schulte, G. (2021). Employing Genetically Encoded, Biophysical Sensors to Understand WNT/Frizzled Interaction and Receptor Complex Activation. In: Schulte, G., Kozielewicz, P. (eds) Pharmacology of the WNT Signaling System. Handbook of Experimental Pharmacology, vol 269. Springer, Cham. https://doi.org/10.1007/164_2021_534

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