Regulation of and signal transduction pathways from cell-cell adhesions

Lead Research Organisation: MRC Cell Biology Unit

Abstract

In society, each of us makes contact with other people through communication and the exchange of information. In the same way, cells in our body interact with their neighbours and this can influence whether a cell grows, changes into another kind of cell or even dies. Exchange of information between cells occurs in many ways, but one essential interaction is through direct cell-cell contacts. This leads to intimate cell-cell adhesion and this allows individual cells to form complex three-dimensional structures that we call tissues. The points of contact between cells are not, however, static, but can be modulated and rearranged particularly during embryonic development. It is also clear that the loss of proper cell-cell contact can lead to uncontrolled cell growth and cancer. In our laboratory, we are trying to identify how new contacts are formed between cells, how these contacts affect the behaviour of the cells and finally how disruption of contacts can lead to abnormal growth and perhaps cancer.

Technical Summary

Cell-cell adhesions complexes are crucial for the assembly of individual cells into three-dimensional tissues. However such complexes are not just glue connecting neighbouring cells, they also have a positive role in constructing diverse and intricate forms of tissues and are dynamically regulated, during cell migration and differentiation for example. Furthermore, cell-cell adhesion complexes are involved in many other processes, such as cell polarity, proliferation, differentiation, and apoptosis. It has also been realized that the loss of epithelial differentiation in carcinomas is often a consequence of reduced intercellular adhesion and indeed some components of cell-cell adhesions function as tumour suppressor proteins (e.g. E-cadherin). The goal of my research group is to answer the following questions centred around cell-cell adhesions: How are cell-cell adhesions dynamically regulated? What molecular mechanisms are involved in disrupting cell-cell adhesions? How do cell-cell adhesions modulate signal transduction pathways controlling proliferation and differentiation?||We recently revealed that specific phenomena are observed at the interface between normal and RasV12-transformed epithelial cells (Hogan et al., 2009, Nature Cell Biology). In the majority of cancers, transformation occurs in a single cell within an epithelial cell sheet. However, it is not known what happens at the interface between normal and transformed cells once the initial transformation has occurred. Using MDCK epithelial cells that express oncogenic Ras (RasV12) in a tetracycline-inducible system, we have investigated the cellular processes arising at the interface between normal and transformed cells. We show that two independent phenomena occur in a non-cell-autonomous manner; when surrounded by normal cells, RasV12 cells are either apically extruded from the monolayer, or form dynamic basal protrusions and invade the basal matrix. Neither apical extrusion nor basal protrusions are observed when RasV12 cells are surrounded by RasV12 cells. We show that Cdc42 and ROCK play a vital role in these processes. We also demonstrate that E-cadherin knockdown in cells surrounding RasV12 cells reduces the frequency of apical extrusion, while promoting basal protrusion formation and invasion. These results indicate that RasV12-transformed cells are able to recognise a difference with normal cells and consequently leave epithelial sheets either apically or basally in a cell-context-dependent manner.

Publications

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Title anti-Hakai antibody 
Description We produced polyclonal anti-Hakai antibody that is suitable for Western blotting and immunofluorescence. We sold this antibody to the company (HyCult biotechnology) through MRC technology. I heard that some researchers are using this antibody for their research. 
Type Of Material Antibody 
Year Produced 2006 
Provided To Others? Yes  
Impact The antibody has been distributed to other scientists. 
 
Description Regulation of and signal transduction pathways from cell-cell adhesions 
Organisation HyCult Biotech
Country Netherlands 
Sector Private 
PI Contribution We provided antibodies to this company.
Impact We have sold anti-hakai polyclonal antibody to the company through MRC Technology.
Start Year 2006
 
Description A newspaper article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact I was interviewed and our work was described in Daily Express.

I believe some of the audience recognized our work profoundly.
Year(s) Of Engagement Activity 2009