Antagonism of PI 3-kinase signalling by PTEN and SHIP2

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The human body is made up of cells which form the tissues and organs. The different tissues of the body have developed to perform specialised functions which must be coordinated for the organism as a whole to function efficiently and survive. Cell signalling is the process by which cells in our bodies communicate with one another and signal transduction is the means by which a specific signal (perhaps a hormone, such as insulin), arriving at its target tissue, is interpreted to elicit a particular response. Defects in cell signalling are common causes of important human diseases such as cancer and diabetes. We are studying the details of a signal transduction process which malfunctions in more than 50% of human tumours and which accounts for many of the effects of insulin produced after a meal. The central character of this response is a fatty substance or lipid called PIP3 which is made by enzymes called PI 3-kinases. When this substance is produced at the correct time, in the right part of the cell and in small, but sufficient amounts it triggers normal cell responses, but too much, in the wrong place or at an inappropriate time can lead to or promote the development of a tumour. On the other hand, producing too little in response to insulin can be a cause of diabetes. Maintaining this delicate balance of PIP3 involves the PI 3-kinase enzymes which make PIP3 and enzymes called phosphatases which remove it. We are studying the factors which regulate two classes of PIP3 phosphatase called PTEN and SHIP2. PTEN is a tumour suppressor that is mutated or absent in many different kinds of human tumour. We use tissue culture cells to study PTEN and SHIP2 regulation and epithelial cells (the source of most solid tumours) as simple models of disease to examine the consequences of defects in PIP3 phosphatase activity. Lastly, we are developing unique mouse models harbouring specific defects in the PTEN gene to validate the physiological significance of our work using cultured cells. Because of its importance in human disease many pharmaceutical companies are developing drugs which block the PI 3-kinase signalling pathway including inhibitors, currently in clinical trials as anti-cancer or anti-inflammatory agents, of PI 3-kinases themselves. My group has a longstanding, active collaboration with a consortium of 5 international companies to accelerate their drug discovery endeavours in this field.