Molecular mechanisms of Wnt signal transduction
The Wnt signalling pathway controls animal development and tissue homeostasis, and is also a major cancer pathway. Its key effector is β-catenin, which is stabilized in response to Wnt stimulation; it thus binds to TCF factors in the nucleus, and functions as a co-activator to mediate Wnt-induced transcription. Inappropriate activation of β-catenin can cause cancer in many human tissues, most notably colorectal cancer.
We study the functions of individual Wnt signalling components and their molecular interactions, using cell-biological, biochemical and structural approaches, as well as fly and mouse animal models. One focus is on the role of Dishevelled, a dynamic polymeric adaptor that transduces the Wnt signal from the plasma membrane to the Axin complex, which also contains the Adenomatous polyposis coli (APC) tumour suppressor and inactivates β-catenin.
Our other focus is on the mechanism of β-catenin-mediated transcription, and how this process may be controlled by the histone-decoding Pygo-BCL9 complex, and by ubiquitin turnover mediated by APC-associated Trabid.
We aim to develop the potential of these Wnt signalling components as drug targets and, ultimately, to discover small molecules that inhibit their interactions and signalling activities.
- de la Roche, M., Rutherford, T.J., Gupta, D., Veprintsev, D.B., Saxty, B., Freund, S.M. and Bienz, M. (2012)
An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid.
Nature Commun 3: 680.
- Tran, H., Hamada, F., Schwarz-Romond, T. and Bienz, M. (2008)
Trabid, a new positive regulator of Wnt-induced transcription with preference for binding and cleaving K63-linked ubiquitin chains.
Genes & Development 22: 528-542.
- Fiedler, M., Mendoza-Topaz, C., Rutherford, T.J., Mieszczanek, J. and Bienz, M. (2011)
Dishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in down-regulating β-catenin.
Proc Natl Acad Sci U.S.A. 108: 1937-1942.
- Julius Mieszczanek
- Marc Fiedler
- Ashraf Ibrahim
- Benjamin Moore
- Nikola Novcic
- Moore van Tienen
- Melissa Gammons
- Miha Renko
- Joshua Flack