The role of cortactin in endolysosomal compartment regulation

Abstract

The branched actin regulator cortactin is a central element connecting signaling pathways with the actin cytoskeleton and plays a role in diverse cellular processes. Cortactin-mediated actin assembly is known to contribute to cancer aggressiveness by regulating secretion of molecules that promote cell motility, invasion, and tumor growth. To better understand the role of cortactin in protein secretion, I focused on molecular and cellular mechanisms underlying cortactin-mediated regulation of protein transport in this dissertation. I demonstrated that cortactin-mediated branched actin assembly regulates late endosomal/lysosomal compartment maturation and trafficking, and subsequent retrograde transport to the Golgi complex. In addition, I identified a novel molecular mechanism by which cortactin control of actin dynamics on late endosomes is regulated by the phosphoinositide PI(3,5)P2. Using a combination of biochemical and cellular imaging approaches I demonstrated that PI(3,5)P2 removes cortactin from late endosomal branched actin networks by competing with actin filaments for binding to cortactin. This interaction promotes net disassembly of branched actin networks at late endosomal membranes. Overall, these findings suggest that cortactin-PI(3,5)P2 interactions regulate actin dynamics on late endosomal membranes by promoting net actin turnover, thereby promoting late endosomal/lysosomal compartment maturation and trafficking.