Project description
Understanding the impacts of beta-catenin condensation
Beta-catenin, or β-catenin, is a key signal-transduction protein that is necessary in the majority of the cells in the body. It plays a critical role in the highly conserved Wnt-signalling pathway, regulating cell fate specification, proliferation and differentiation during development and in various adult tissues. To achieve this role, β-catenin is present at the plasma membrane in the cytoplasm and in the cell nucleus. In all these sites β-catenin needs to be highly localized and organized. How this organization takes place is currently unknown. The EU-funded Catenin-Condensation project aims to uncover how the condensation of β-catenin into protein droplets, at the membrane and in the cytoplasm, impacts the Wnt signalling pathway. The proposed work will contribute to understanding cancer etiology. What is more, deeper knowledge of the fundamental Wnt signalling pathway can have a profound impact on the understanding of embryonic development, adult regeneration and cancer.
Objective
The Wnt-signaling pathway is a key determinant of cell identity and proliferation. However, when aberrantly activated it drives malignant cell proliferation in gastrointestinal cancer, breast cancer, melanoma and leukemia. The key effector protein of the Wnt pathway is β-catenin, which is continuously degraded in unstimulated cells, but in stimulated cells it accumulates and translocates to the nucleus where it activates transcription. A growing body of literature indicates that transcription factors and co-activators interact through the formation of biomolecular condensates. These are membraneless organelles that concentrate and compartmentalise components through weak, but multivalent interactions. Recently, I have shown that β-catenin forms condensates with Mediator co-activator to specifically activate transcription. However, how this new mode of β-catenin interactions influences the rest of the Wnt-pathway is currently unknown. The overarching goal of this proposal is to uncover how β-catenin condensation impacts the Wnt-signaling pathway. I will investigate the consequences of β-catenin condensation for its cytoplasmic regulation by the destruction complex, study how it affects β-catenin co-factor interactions in the nucleus and determine the effect of oncogenic Wnt-signaling on β-catenin condensates. The proposed work will uncover if β-catenin condensation has a function in the Wnt-signaling pathway outside the nucleus, its effect on co-factor interactions and elucidate how it might contribute to cancer etiology. Deeper understanding of the fundamental Wnt-signaling pathway will have a profound impact on our comprehension of embryonic development, adult regeneration and cancer.
Fields of science
- medical and health sciencesclinical medicineoncologyskin cancermelanoma
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencesdevelopmental biology
- medical and health sciencesclinical medicineoncologybreast cancer
- medical and health sciencesclinical medicineoncologyleukemia
Programme(s)
Funding Scheme
MSCA-IF-EF-RI - RI – Reintegration panelCoordinator
3584 CX Utrecht
Netherlands