The ATP receptor P2Y11 engages nonapoptotic functions of Fas

We are investigating the P2Y11 receptor, which is found on the cell surface of various human cell types. It is particularly common on immune cells. This receptor has not been found in mice and other rodents. The P2Y11 receptor binds extracellular adenosine triphosphate (ATP), a danger signal that increases with cell stress. Since ATP is derived from the molecule purine, P2Y11 is also referred to as purinergic receptor (or purinoreceptor). Activated by extracellular ATP, it transmits signals into the cell interior by coupling to so-called G proteins. The signals triggered by the P2Y11 receptor then activate cell-protective programmes so that the cell can better cope with the existing stress. In the planned project, we want to study the mechanisms triggered by the P2Y11 receptor that protect the cell and ensure its survival. Another receptor, Fas (CD95), is the focus of our interest. Although it is actually known as a death receptor that causes the death of defective or infected cells, Fas may also promote cell survival. In our preliminary investigations, we have found many indications that the active P2Y11 receptor also involves the Fas receptor during signal transduction into the cell`s interior, which subsequently works for the P2Y11 receptor and activates genes that enable the execution of cell protection or survival programmes. Once we have characterised the signalling pathways of the P2Y11 receptor and the resulting cell programming, we hope to apply our findings in two specific models. The human liver has a special potential for regeneration, i.e. it can repair even quite extensive tissue damage. Our preliminary work indicates that the P2Y11 receptor in cooperation with the Fas receptor drives liver regeneration by reacting to extracellular ATP, which is released from the cells when tissue damage occurs. In the second model, we investigate the role of the P2Y11 receptor in the differentiation of specific immune cells, the monocytes or macrophages, which are derived from the monocytes in a conversion/differentiation process. We are particularly interested in whether the P2Y11 receptor is responsible for the longevity of certain macrophage populations and how it controls the mostly anti-inflammatory functions of these cells. The signalling pathways of the P2Y11 receptor have not been explored sufficiently. In fact, the interaction of the P2Y11 and Fas receptors is an absolute novelty. If we understand these mechanisms better, it will also be easier to intervene therapeutically and either inhibit (e.g. in cancer) or stimulate (e.g. in tissue regeneration) the survival of cells. Furthermore, the anti-inflammatory potential of the P2Y11 receptor can be exploited in the treatment of autoimmune and infectious diseases.

In the recently completed project, we studied the P2Y11 receptor, which is found on the cell surface of various human cell types. The P2Y11 receptor is particularly abundant on immune cells. This receptor has not been found in mice or other rodents. The P2Y11 receptor binds extracellular adenosine triphosphate (ATP), a danger signal that increases during cell stress. Because ATP is derived from the molecule purine, P2Y11 is also known as a purinergic receptor (or purinergic receptor). When activated by extracellular ATP, it transmits signals into the interior of the cell by coupling to G-proteins. The signals generated by the P2Y11 receptor then activate cell-protective programmes to help the cell cope with stress. Over the past 4 years, we have been studying the mechanisms triggered by the P2Y11 receptor that protect the cell and ensure its survival. The focus of our interest has been another receptor called Fas (CD95). Although known as a death receptor that causes the death of defective or infected cells, Fas can also promote cell survival under certain circumstances. We have found a lot of evidence that the active P2Y11 receptor also involves the Fas receptor in the transmission of signals into the interior of the cell, which then acts on the P2Y11 receptor and activates genes that in turn enable the implementation of anti-inflammatory or blood vessel-forming programmes and thus tissue repair. Using gene expression analysis and complementary cell biological and immunological methods, we have characterised the signalling pathways of the P2Y11 receptor and the resulting cell programming. The most important finding of our project is that P2Y11 and Fas also activate the IL-1 receptor, the EGF receptor and the chemokine receptor CXCR7. We also found that the complex signalling pathway initiated by P2Y11 and Fas is counteracted by the chemokine receptor CXCR4. Our latest findings suggest that the P2Y11 receptor may also control the development and function of tumour-associated macrophages. The signalling pathways of the P2Y11 receptor have been poorly understood. The interplay between P2Y11 and the Fas receptor that we have now described is actually an absolute novelty. If we know and understand the key players and their counterparts in this pathway better, we will be able to intervene more effectively therapeutically and either inhibit cell survival (e.g. in cancer) or stimulate it (e.g. in tissue regeneration). The anti-inflammatory potential of the P2Y11 receptor could also be exploited in the treatment of autoimmune and infectious diseases.