New signalling mechanisms of pi 3-kinase

PI 3-kinases (PI3Ks) generate lipids in cell membranes, controlling many biological functions. The PI3K signalling axis is important, amongst others, in immune cell signalling and is one of the most frequently deregulated pathways in cancer. The lipids produced by PI3Ks coordinate the localisation and function of multiple effector proteins, which bind these lipids through specific lipid-binding domains. These include protein kinases of the Ser/Thr and the Tyr kinase families (such as Akt/PKB and Btk, respectively), adaptor proteins (such as Gab2) and regulators of small GTPases (GAPs and GEFs). Thus far, a large focus of PI3K studies has been on the protein kinase Akt/PKB as a downstream target of PI3K, largely because of the availability of phospho-specific antibodies that allow us to monitor the activation of this kinase and its downstream targets in a relatively straightforward manner. Because the majority of published studies focus on this area, this has given rise to the skewed view that the PI3K pathway 'equals' that of Akt/PKB. This is a gross simplification, and indeed, evidence is emerging for the importance of Akt-independent pathways of PI3K signalling. For example, PI3K can be oncogenically mutated and activated in cancer, but this does not necessarily correlate with an activation of Akt/PKB (Cancer Cell 2009:16:21). As mentioned above, Akt-independent PI3K pathways are known but their relative importance is most often not clear. It cannot be excluded that there are additional pathways downstream of PI3K that remain to be uncovered. This is a fundamental science project that aims to discover new signalling pathways of PI3K, with focus on the p110alpha (p110a) isoform of PI3K. For these studies, we will exploit the availability of a new mutant mouse line that we have generated (unpublished), which carries an inducible oncogenic p110a PI3K allele, and cell lines derived thereof. These studies will be complemented by other cell lines and new mutant mice that we have generated, which carry in-activating alleles of p110a and other PI3K isoforms. Other than providing mechanistic insight into a key signalling pathway, this fundamental science project is also anticipated to allow the identification of molecular alterations induced by p110a (oncogenic or wild-type) which can be used as biomarkers for cancer diagnosis and therapy.