The ability of the cell to break symmetry and properly establish a polarized localization of different signaling molecules is critical for efficient migration, division, axon guidance and various immune responses. Phosphoinositidemediated signaling pathways are known to play a vital role in setting the polarity circuit during cell migration and division. When the PM lipids that regulate these processes are spatially or temporally misregulated, pathologies can occur, including tumorigenesis. The work described here strongly suggests that the PM PI(4,5)P2 levels set a threshold for cell excitability. PI(4,5)P2 levels below a specific threshold trigger Ras GTPase and PI3K activity, contributing to signaling networks that lead to branching actin polymerization and cell protrusions. Abovethreshold PI(4,5)P2 levels support regulators that contribute to quiescent membrane activity and actomyosin contraction. Additionally, the presented data
shows for the first time, a correlation between the PM PI(4,5)P2 threshold and rates of phosphatidylserine (PS) exposure in health and disease. Receptormediated cell stimulation triggers PS exposure to the outer leaflet of the PM. Interestingly, the same responses were achieved upon the synthetic lowering of the PM PI(4,5)P2 levels. Taken together, this work proposes a synergistic role of the
PM PI(4,5)P2 threshold and the rate of PS exposure that is critical for altering cell polarity and changes in cell morphology. These outcomes present a rationale for the clinical investigation of implicating the anionic membrane lipids, the phosphoinositide PI(4,5)P2 and the phospholipid PS, as novel therapeutic targets for fighting tumorigenesis and cancer metastasis.
|Commitee:||Myers, Kenneth, Mercier, Isabelle, Wang, Zhihong, Tomsho, John|
|School:||University of the Sciences in Philadelphia|
|Department:||Cell & Molecular Biology|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 81/2(E), Dissertation Abstracts International|
|Keywords:||Cancer, Cell migration, Cell morphology, Cell polarity, Phosphoinositides, Phospholipids|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be