Dissertation/Thesis Abstract

Tuning of the Anionic Membrane Lipids PI(4,5)P2 and Phosphatidylserine Establishes Polarized Morphologies and Regulates Cell Migration
by Beshay, Mariam, Ph.D., University of the Sciences in Philadelphia, 2019, 100; 22617179
Abstract (Summary)

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.

Indexing (document details)
Advisor: Janetopoulos, Christopher
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
Source Type: DISSERTATION
Subjects: Cellular biology
Keywords: Cancer, Cell migration, Cell morphology, Cell polarity, Phosphoinositides, Phospholipids
Publication Number: 22617179
ISBN: 9781085674300
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