Research Group MAURICE
Faculty of Medicine, UMC Utrecht, Dept. of Cell BiologyContact: Dr. Madelon Maurice
E-mail: M.M.Maurice@umcutrecht.nl
Website: http://www.cellbiology-utrecht.nl/groups/maurice/index.html
General research focus: Cell biology of Wnt signalling in development and cancer
Wnt proteins dictate critical cell growth and lineage decisions during development. Aberrant activation of the Wnt pathway is a frequent cause of cancer. Proper cell-cell communication by Wnt signalling occurs through secretion by restricted groups of cells and subsequent spreading of Wnt molecules into adjacent tissue where genetic programs are induced upon binding of Wnt to specific receptors.
We address a number of key aspects of both the secretion of Wnts and the early events induced by binding of Wnt to their receptors at the cell surface. We focus on the poorly understood relationship between subcellular protein localization and its bearing for protein function in the Wnt cascade. In an interdisciplinary approach, linking biophysics and in vivo cell biology, we will determine how mutational damage of Wnt cascade regulatory proteins affects their structural stability and how this relates to their turnover and physiological function in the cell.
Research lines:
1. Wnt secretion
Wnt molecules are lipid-modified, which makes them unique among other families of secreted signalling molecules. Unknown is how lipidation affects intracellular transport and secretion of Wnts. We combine methods of biochemistry, proteomics, and gene silencing with the resolution power of advanced immuno-electron microscopy (EM) techniques to analyze the molecular machinery involved in intracellular transport and secretion of Wnt molecules. We include genetic animal models (Drosophila) to study Wnt secretion in polarized cells in vivo at the ultrastructural level. We aim to uncover where key maturation steps of Wnts occur, which proteins are locally involved, and how they direct sorting, modification and secretion of Wnts.
2. Signal transduction by Wnts
In cells that receive Wnt signals, the upstream molecular events that couple receptor-ligand binding to the transcriptional activation of the key player of the pathway, -catenin, arepoorly understood. We have identified a novel deubiquitinating enzyme, involved in ubiquitin removal form its substrates, as a key regulatory tumour suppressor that acts upstream in the Wnt pathway. By using advanced proteomic and imaging techniques, we aim to elucidate how ubiquitination regulates Wnt signalling.
3. Biophysical analysis of damaged Wnt cascade proteins
The relation between biophysical protein stability and protein stability in vivo is a crucial but poorly understood fundamental question. Protein damage induced by point mutations is a major cause of human cancer. Does protein damage such as it is caused by oncogenic point mutations alter protein stability? What are the consequences for protein function in the cell? Does the biophysical protein stability matter in a physiological environment where turnover of key regulators is always strictly controlled? We address these questions for key regulatory proteins of the Wnt cascade in an interdisciplinary collaboration with Dr Stefan Rudiger, Cellular Protein Chemistry, University Utrecht.
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