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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03182015-122017 |
| Date | 19 March 2015 |
| Creators | Hong, Nan Hyung |
| Contributors | Rebecca S. Cook, Matthew J. Tyska, Anne K. Kenworthy, Vito Quaranta, Alissa M. Weaver |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf, video/quicktime |
| Source | http://etd.library.vanderbilt.edu/available/etd-03182015-122017/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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