Oncogenic Activation Mechanisms of Phosphoinositol-3-Kinase
Abstracts
Initial Award Abstract |
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Cigarette smoking is the major cause of lung cancer. Lung cancer denominates the uncontrolled growth of lung tissue in the form of tumors. Often the primary tumors metastasize, i.e. they spread to other parts of the lung or different organs, where they form secondary tumors and thereby destroy healthy tissue. Most lung tumors are diagnosed relatively late at a time when metastases have already formed. At this stage there are very few or no therapies that effectively slow down cancer progression or even cure cancer. This is why mortality of lung cancers is particularly high, with five-year-survival rates being as low as 15 %. It is therefore a central challenge to understand the mechanisms that underlie tumor growth and metastasis. Knowledge of the cellular components and their respective role in cancer progression will help to devise strategies to target these components. Cigarette smoke induces mutations in the genetic material. These changes can lead to unbalanced proliferation or survival signals in the cell causing tumor formation. Such changes can, for example, induce pathologically up-regulation of the enzyme phosphoinositol-3-kinase. This enzyme phosphorylates special lipids – called phosphoinositides - at the plasma membrane. The modified lipids then recruit effector proteins to the plasma membrane that regulate cell proliferation, cell migration and survival. To date, it is not very well understood how PI3K is recruited to the plasma membrane, which is the first essential step of its activation mechanism. Furthermore mutations of PI3K that very moderately increase its activity induce cancer. It remains unclear how such a small change can lead to tumor development. We propose to elucidate how PI3K is recruited to membranes and to study the activation mechanism of PI3K including potential signal amplification mechanisms that are necessary for tumorigenesis. Furthermore, we are interested in a particular effector protein, Tks5, which is recruited to the plasma membrane after PI3K activation. Several findings have suggested that Tks5 is essential for tumors to invade surrounding tissue, a critical step in metastasis. We thereby hope to identify the components of a signal transduction pathway that is essential for metastasis. Inhibition of these components might help to substantially slow and completely inhibit cancer cell dissemination and thereby greatly enhance survival and cure of lung cancer patients. |
