More than half of all human tumours arise when a single fatty molecule called PIP3 builds up in the wrong place or at the wrong time inside cells. This molecule is normally kept in check by two enzymes, PTEN and SHIP2, which act as molecular brakes. When PTEN is missing or faulty—as it is in many cancers—the brakes fail and cells grow uncontrollably. The same signalling pathway also controls how the body responds to insulin after a meal, meaning defects here can contribute to diabetes as well. This project studies exactly how PTEN and SHIP2 are regulated, using cultured cells and specially engineered mice with precise defects in the PTEN gene. This is fundamental science. It does not aim to produce a drug or a diagnostic test tomorrow. But because the PI 3-kinase pathway is already a target for anti-cancer and anti-inflammatory drugs in clinical trials, understanding how PTEN and SHIP2 work could help pharmaceutical companies design more effective inhibitors. The research group already collaborates with five international companies to accelerate that work. A clearer picture of these molecular brakes could eventually make existing cancer treatments more precise and reduce side effects.
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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.
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