Final Report Summary - PI3K-III COMPLEX (The PI3K-III complex: Function in cell regulation and tumour suppression)
The main objective of the present project was to identify the mechanisms of class III phosphatidylinositol 3-kinase (PI3K-III) in tumour suppression. Our studies have revealed that proteins recruited by the catalytic product of PI3K-III, the lipid phosphatidylinositol 3-phosphate (PI3P), controls several processes that play a role in tumour suppression. We had previously found that PI3P recruits the endosomal sorting complex required for transport (ESCRT) machinery to endosomes for lysosomal sorting of ubiquitinated growth factor receptors. In the present project we found that the ESCRT machinery also mediates lysosomal downregulation of ubiquitinated fibronectin receptors (α5β1-integrin) to control cell migration. This was surprising since lysosomal degradation of α5β1–integrin has previously not been detected. In collaboration with a young scientist in our Department, Jørgen Wesche, we have also found that PI3P serves as intermediate in production of phosphatidylinositol 5-phosphate, a lipid that turned out to be a potent regulator of cell migration downstream of activated fibroblast growth factor receptors. Together with another young scientist, Anne Simonsen, we have identified the PI3P-binding protein Alfy as a novel regulator of autophagy, a process previously shown to play a role in tumour suppression. Finally, our research has uncovered a conceptually interesting function of PI3P in cytokinesis, the final stage of the cell division process. We identified the PI3P-binding protein FYVE-CENT as a regulator of the abscission step of cytokinesis whereas another PI3P-binding protein, ANCHR, was identified as a crucial component of the abscission checkpoint in cytokinesis. Our studies have also revealed the molecular mechanisms by which FYVE-CENT and ANCHR control cytokinesis. In summary, the project has identified novel roles for PI3P-binding proteins in cell signalling, endocytic trafficking, autophagy and cytokinesis. All of these processes need to be functional in order to prevent tumourigenesis, and PI3K-III thus functions as tumour suppressor by regulating effectors in multiple tumour suppressor pathways.