BIOLOGICAL SCIENCES
THE RHO FAMILY GEF ASEF2 REGULATES ADHESION DYNAMICS AND THEREFORE CELL MIGRATION BY MODULATING RAC AND RHO ACTIVITY
JEANNE MALLOY BRISTOW
Dissertation under the direction of Assistant Professor Donna J. Webb
The Rho family of small GTPases, including Rac, Cdc42, and Rho, are key regulators of cell migration and its underlying processes. By modulating the actin cytoskeleton, these GTPases control cell polarization, leading edge protrusion, and cell-matrix adhesion turnover. GTPases act as molecular switches whose activity is tightly regulated by their bound guanine nucleotide state. Guanine nucleotide exchange factors (GEFs) tightly regulate GTPase activity by facilitating the exchange of bound GDP for GTP. Asef2 is a recently identified Rho family GEF that has been shown to activate Rac and Cdc42. However, its function as a regulator of cell migration and adhesion dynamics is poorly understood. Immunofluorescence microscopy revealed that Asef2 localizes with actin and Akt at the leading edge of migrating HT-1080 human fibrosarcoma cells. Our data indicate Asef2 activates Cdc42 and Rac and indirectly inhibits Rho through a Rac-mediated pathway. We have shown that Asef2 promotes migration and rapid adhesion turnover in a Rac-dependent manner. Further, Asef2-mediated random migration and adhesion turnover effects are dependent on a previously unknown mechanism requiring Asef2-mediated Rac, PI3K, and Akt activation leading to Rho inhibition. Together, these data indicate a role for Asef2 as an important regulator of cell migration and adhesion dynamics as it coordinately regulates the activity of Rho family GTPases.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-12022009-125315 |
| Date | 08 January 2010 |
| Creators | Bristow, Jeanne Malloy |
| Contributors | Christopher Janetopoulos, Anne K. Kenworthy, James G. Patton, Donna J. Webb, 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-12022009-125315/ |
| Rights | unrestricted, 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. |
Page generated in 0.0014 seconds