Wnt signalling cascades control animal development and stem cell compartments in many tissues, and are amongst the most ancient and highly conserved signalling pathways within the animal kingdom. One key effector is beta-catenin, which is stabilised in response to Wnt stimulation; beta-catenin thus binds to TCF factors at Wnt-responsive enhancers to switch on the transcription of linked genes. Inappropriate activation of beta-catenin can cause cancer in many human tissues, most notably colorectal cancer.
We study the molecular functions of individual Wnt signalling components and their mutual interactions, using cell-biological, biochemical and structural approaches, as well as fly and mouse animal models. One focus is on the role of Dishevelled in assembling signalosomes by dynamic polymerization during Wnt signalling, to block the function of Axin degradasomes in destabilising beta-catenin.
Another focus is on the Wnt enhanceosome and the role of its core component Chip/LDB-SSDP in responding to Wnt signalling through Pygo-BCL9 and integrating this with other signalling inputs. Ultimately, our work is aimed at identifying and developing the potential of new Wnt signalling components as therapeutic targets in cancer.
Selected Papers
- Bienz, M. (2020)
Head-to-tail polymerization in the assembly of biomolecular condensates.
Cell 182: 799-811. - van Dop, M., Fiedler, M., Mutte, S., de Keijzer, J., Olijslagers, L., Albrecht, C., Liao, C-Y., Janson, M., Bienz, M. and Weijers, D (2020)
DIX domain polymerization drives assembly of plant cell polarity complexes
Cell 180: 427-439 - Mieszczanek J, van Tienen LM, Ibrahim AEK, Winton DJ and Bienz M (2019)
Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models
Nature Comm 10: 1038 - Flack JE, Mieszczanek J, Novcic N and Bienz M (2017)
Wnt-dependent inactivation of the Groucho/TLE co-repressor by the HECT E3 ubiquitin ligase Hyd/UBR5
Mol Cell 67: 181-193 - van Tienen LM, Mieszczanek J, Fiedler M, Rutherford TJ & Bienz M (2017)
Constitutive scaffolding of multiple Wnt enhanceosome components by Legless/BCL9
eLife, e20882 - Gammons M, Renko M, Johnson CM, Rutherford TJ & Bienz M (2016)
Wnt signalosome assembly by DEP domain swapping of Dishevelled
Mol Cell 64: 92-104 - Fiedler, M., Graeb, M., Mieszczanek, J., Rutherford, T.J., Johnson, C.M. and Bienz, M. (2015)
An ancient Pygo-dependent Wnt enhanceosome integrated by Chip/LDB-SSDP
eLife, e09073
Group Members
- Marc Fiedler
- Elsa Franco Echevarria
- Melissa Gammons
- Tiemei Li
- Julius Mieszczanek