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- Professor of Cell Biology
- Inst Ophthalmology - Cell Biology
- Institute of Ophthalmology
- Faculty of Brain Sciences
Epithelial cells perform crucial functions in organs and tissues, ranging from the liver and the intestine, to the brain and the retina. To perform their physiological functions, epithelial cells need to polarise – form distinct cell surface domains that are biochemically and functionally distinct – and adhere to each other to form continuous sheets of differentiated cells that function as barriers between body compartments and to the environment. Many diseases originate in or affect particular epithelia, ranging from cancer to chronic, inflammatory and age-related diseases, such as asthma and age-related retinal degenerations. We are interested in different aspects of epithelial cell biology and have made significant contributions to the understanding of how epithelial cells polarise and generate distinct cell surface domains, how epithelial cells adhere to each other to form functional barriers, how such mechanisms contribute to the regulation of epithelial cell behaviour and differentiation, and how they are affected by and contribute to disease.
Since I started my laboratory at UCL in 2001, we have focused on the structure and functions of tight junctions and, particularly, on how tight junctions receive signals that guide junction assembly and function and how they signal to the cell interior to guide cell proliferation and survival. This led to important findings that provided new insights into the structure and function of tight junctions.
Among which was the discovery of ZONAB, the first description of a signalling mechanism by which tight junctions can directly regulate gene expression. We demonstrated that ZONAB is activated during proliferation and stress signalling, and regulates genes transcriptionally and posttranscriptionally that are important for cell proliferation and survival (e.g., cyclin D1, PCNA, p21). We also isolated physically and functionally interacting proteins such as the heat shock protein Apg-2, a protein that regulates junction assembly, and the cell cycle kinase CDK4.
We have discovered a new cell-cell adhesion protein, MarvelD3. This protein is a component of tight junctions, the cell-cell junction that mediates epithelial barrier formation. We have demonstrated that this adhesion protein is not a critical component of the actual intercellular barrier but is the cell surface receptor of a new signalling mechanism that regulates MAP Kinase signalling and, thereby, gene expression. This pathway regulates epithelial proliferation and migration, and is an important component of the epithelial stress response.
A main research effort has focused on the molecular mechanisms that regulate epithelial Rho GTPase signalling. Rho GTPases are regulatory switches of central signalling pathways that regulate all aspects of epithelial proliferation, differentiation and survival. However, little had been known about how these common signalling components are regulated and recruited for specific signalling functions. We have discovered multiple regulators that drive specific activation or inactivation of Rho GTPases and, thereby, control epithelial proliferation and gene expression, mitosis and genome integrity, stress response and survival, polarization and morphogenesis.
|1989||PhD||Doctor of Philosophy – Biochemistry||Universitat Basel|