BBB Seminar - Biokjemisk Kollokvium (NBS, Bergen Division): Harald Stenmark
A lipid kinase in membrane dynamics and tumour suppression
Centre for Cancer Biomedicine, University of Oslo
Phosphorylated derivatives of the membrane lipid phosphatidylinositol (PtdIns), known as phosphoinositides, regulate membrane-proximal cellular processes by recruiting specific protein effectors involved in cell signalling, membrane trafficking and cytoskeletal dynamics. Two phosphoinositides that are generated through the activities of distinct phosphoinositide 3-kinases (PI3Ks) are of special interest in cancer research. PtdIns(3,4,5)P3, generated by class I PI3Ks, functions as a tumour promotor by recruiting effectors involved in cell survival, proliferation, growth and motility. Conversely, there is evidence that PtdIns3P, generated by class III PI3K, functions in tumour suppression. Three subunits of the class III PI3K complex (Beclin 1, UVRAG and Bif1) have been independently identified as tumour suppressors, and their mechanism of action in this context has been proposed to entail activation of autophagy, a catabolic pathway that is thought to mediate tumour suppression by scavenging damaged organelles that would otherwise produce reactive oxygen species that cause DNA instability. We have recently obtained evidence for two additional functions of PtdIns3P that might contribute to its tumour suppressor activity. One such mechanism involves ligand-mediated down-regulation of growth factor receptors mediated by the endosomal sorting complex required for transport (ESCRT) machinery. The other and most recent potential tumour suppressor mechanism involves the regulation of cytokinesis, the final stage of cell division. Elucidation of the mechanisms of tumour suppression mediated by class III PI3K and PtdIns3P will help us to identify novel Achilles´ heels of the cell’s defence against tumourigenesis and will be useful in the search for prognostic and diagnostic biomarkers in cancer.
Host: Jaakko Saraste, Department of Biomedicine