Exosomes are extracellular vesicles that carry a variety of RNA and protein cargos, including growth factors, transmembrane proteins, angiogenic factors, proteinases, and microRNA. However, the mechanisms that regulate exosome secretion are still poorly understood. This dissertation work shows that the tumor-overexpressed cytoskeletal protein cortactin promotes exosome secretion. Knockdown or overexpression of cortactin in head and neck squamous cell carcinoma, fibrosarcoma, and breast cancer cells leads to a corresponding decrease or increase in exosome secretion. However, cortactin knockdown does not affect cargo sorting or exosome biogenesis. Rescue experiments carried out by adding purified exosomes back to cortactin-knockdown cells suggest that exosome secretion may account for many functions of cortactin in tumor aggressiveness. Furthermore, live imaging revealed that cortactin controls both trafficking and plasma membrane docking of multivesicular endosomes. Mechanistically, interaction of cortactin with Arp2/3 complex and branched actin is critical for exosome secretion. Also, cortactin, Rab27a, and coronin 1b coordinately control stability of cortical actin multivesicular endosome docking sites along with exosome secretion. Overall, this dissertation identifies molecular and cellular mechanisms important for exosome secretion.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07212016-161343 |
| Date | 26 July 2016 |
| Creators | Sinha, Seema |
| Contributors | Dr. Robert J. Coffey, Dr. Matthew J. Tyska, Dr. Rebecca A. Ihrie, Dr. Alissa M. Weaver, Dr. Rebecca S. Cook |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | video/x-msvideo, application/pdf, application/octet-stream |
| Source | http://etd.library.vanderbilt.edu/available/etd-07212016-161343/ |
| 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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