WNT-mediated signaling relay in stem cells and oncogenesis - from basic biology to applications

Understanding mutant Axin-mediated tumorigenesis

Early stage researcher 2 (ESR2) project

Supervision: Madelon Maurice

Lab webpage:  http://www.cellbiology-utrecht.nl/groups/maurice.html

Aim:
To resolve critical molecular mechanisms by which mutant Axin drives uncontrolled Wnt pathway activation and tumorigenesis.

Methodology:
ESR2 will investigate how a newly designed rescue mutant restores the functional capacity of an Axin cancer mutant to downregulate Wnt pathway activation in cells. ESR2 will: 1) Address how a newly identified suppressor mutation changes Axin cancer mutant conformation to rescue functional activity (collaboration Rüdiger); 2) Examine the role of mutation-induced alterations in the mutant Axin interactome using mass spectrometry and manipulating binding of key partners (collaboration Bryja, international secondment: Friedler); 3) Develop peptide-based strategies to restore Axin cancer mutant structure and rescue activity (collaboration Pepscan, private sector secondment: Isogenica); 4) Assess the role of Axin mutations in mammalian tumorigenesis (collaboration Koo).

Collaborators:
Friedler, Bryja, Isogenica, Pepscan, Koo

Project goals:
ESR2 will identify how mutation-induced conformational changes in Axin drive tumorigenesis and develop reagents that and rescue tumor suppressor activity of mutant Axin.

Risk assessment and contingency plans:
Recombinant Axin fragments for biophysical analysis are available. Mouse models have a high chance of success regarding established Drosophila models. Identification of reagents that rescue Axin suppressor activity is guided by highly promising results with rescue mutants.

Key publications:

1. Koo BK, Spit M, Jordens I, Low TY, Stange DE, van de Wetering M, van Es JH, Mohammed S, Heck AJR, Maurice MM* and Clevers H* (2012) Tumour suppressor RNF43 is a stem cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488:665-669 (*co-corresponding)

2. Tauriello DVF, Jordens I, Kirchner K, Slootstra J, Kruitwagen T, Bouwman, BAM, Rüdiger SGD, Schwamborn K, Schambony A, Maurice MM (2012). Dvl employs its DEP domain and C-terminus to bind a discontinuous motif in the Fz receptor and initiate Wnt/β-catenin signalling. Proc Natl Acad Sci U S A. 109(14):E812-20

3. Tauriello DVF, Haegebarth A, Kuper I, Canninga-van Dijk M, Edelmann MJ, Henraat M, Kessler, BM, Clevers H, Maurice MM (2010) Loss of the tumor suppressor CYLD enhances Wnt/β-catenin signaling through K63-linked ubiquitination of Dvl. Mol Cell 37: 607-619