Leading Edge Dynamics during Spreading and Migration

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Title: Leading Edge Dynamics during Spreading and Migration
Author: Krajcovic, Matej
Advisors: Balaji Rao, Committee Member
David F. Ollis, Committee Member
Jason M. Haugh, Committee Chair
Abstract: Cell migration is an essential part of wound healing and cancer metastasis. Cells interpret adhesive and soluble stimuli from the environment into directed movement. During cell migration, cells protrude in the direction of motion, forming a leading edge, and retract at the trailing edge. The signaling events at the leading edge are crucial for efficient migration. Cells bind to extracellular matrix (ECM) via integrin receptors. Phosphoinositide 3 kinase (PI3K) is activated in fibroblasts during spreading on fibronectin and poly-lysine. Blocking of integrin receptors by β1-integrin antibody inhibits adhesion on fibronectin but not on poly-lysine. PI3K activity is not affected by integrin blocking on poly-lysine. Active Rac, a Rho GTPase, stimulates formation of lamellipodia at the leading edge. We used fluorescent probes for Rac and PI3K in conjunction with total internal fluorescence microscopy (TIRF) to examine spatial distribution of Rac and PI3K. In randomly migrating fibroblasts, Rac and PI3K are co-localized most times in the cell protrusions. The mechanisms governing the formation and disassembly of integrin-ECM adhesion complexes at the protruding leading edge are central to the understanding of cell migration. We have developed a simplified mathematical model that incorporates adhesion and protrusion dynamics mediated by Rac/Pak (p21-activated kinase) signaling at the leading edge. Nascent adhesions either disassemble (turn over) or mature into stable focal adhesions. Stable adhesions can be involved in two distinct pathways of protrusion inhibition. We performed a bifurcation analysis with respect to density of ECM and existence of two possible steady states has been shown. A stochastic version of the model employing the Gillepsie algorithm was developed to model the effect of diffusion in a linear geometry. At certain conditions, multiple states of activation are present within the leading edge.
Date: 2008-10-20
Degree: MS
Discipline: Chemical Engineering
URI: http://www.lib.ncsu.edu/resolver/1840.16/163

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