EUROCORES: The functions of phosphoinositides in tissue morphogenesis and cancer

Membrane dynamics modulate cell polarity, vesicular trafficking, migration, growth, proliferation, differentiation, and more. Of all membrane lipids, phosphoinositides play a central role in these processes (Wymann & Marone 2005 Curr Opin Cell Biol; Lindm o & Stenmark 2006 J Cell Sci; Simonsen & Stenmark 2007 Nat Chem Biol). Although a role for the prominent 3-phosphorylated phosphoinositides such as PtdIns(3,4,5)P3 and PtdIns(3)P has been highlighted in physiology and disease (Wymann et al. 2003 TiPS), dy namics and localization of these lipids are still poorly understood. TraPPs will provide a dynamic and refined view of phosphoinositide flux, and required lipid modifying enzymes, e.g. PI3Ks, lipases, and lipid phosphatases. Lipid-modifying enzymes will b e targeted dynamically to distinct cellular locations, and lipid-interacting proteins shall be manipulated to display their free or lipid-bound state. Finally, the activity state of phospholipid-modifying enzymes will be imaged by the formation of enzyme- substrate complexes in living cells (Yudushkin et al., 2007, Science). Activation of lipid modifying enzymes will be linked to localized upstream signalling and specific cell responses. Cellular, genetic fly and mouse models will be used to validate the u ncovered molecular mechanisms. This work provides the basis for a broader systems biology approach of lipid signaling, and will elucidate dynamic cellular processes relevant to cancer and inflammation.