Unravelling c-Met signalling from autophagic endomembranes

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Our body is composed of billions of cells. These cells are constantly exchanging information in the form of signals, which is crucial for them to act in a coordinated fashion. These signals can induce cell multiplication, movement, and cell death. This communication is often initiated by the interaction of two proteins: a ligand and a receptor. Ligands bind to the receptors, which are normally present at the surface of cells, to transmit signals from outside the cell. The receptors then activate additional proteins, called signal transducers, to transmit the signals to the inside of the cell, where they are interpreted and alter the cell's behaviour. Cells must tightly control the activity of these receptors because deregulated receptor activity can lead to diseases, such as chronic inflammation or cancer. Thus, there is a need to better understand how receptors operate so that they can be corrected when they go wrong. A cell is like a town, and each building block in a cell has a role. Autophagy is one of these blocks; it is like a household waste recycling centre: cell waste are sent to autophagic sites to be destroyed and recycled. Surprisingly we recently find out that in cancer cells, these recycling centre were hijacked for some "illegal activities": we have found that receptors responsible for cancer go there not to be degraded but on the contrary to be even more active. This new scientific concept changes our understanding of how receptors operate. It opens new challenges to understand how receptors transmit information to signal transducers inside the cell, and why receptor activity on autophagic sites, as opposed to activity at the cell surface, is required to modulate cell behaviour. We propose investigating this concept using one receptor model, c-Met. This receptor plays a major role in controlling cell growth, cell survival and cell movement, thus contributing to proper organ function and renewal. It is also deregulated in diseases such as chronic inflammation and cancer and therefore need to be targeted in these conditions. We aim to fully understand the mechanisms necessary for c-Met to transmit signals from autophagic sites. To achieve our objectives we will use state of the art cell biology, imaging and biochemistry techniques. In particular, we will use a novel technique that allows the capturing of all the partners of c-Met that are present on autophagic sites.Our work will lead to the discovery of novel molecular mechanisms controlling receptor activity. Our results should benefit researchers working on receptors, signal transducers, cell growth, cell survival and cell movement, both within the UK and internationally. Since autophagic c-Met activity accounts for the aggressiveness of certain tumours, our research could also benefit researchers working on cancer. Furthermore, given that c-Met is necessary for proper organ function and renewal, our results may have an impact in the fields of regenerative medicine and ageing. Thus the beneficiaries of this research include pharmaceutical companies, the public health domain (NHS) and patients.