Growth and Dynamics of Extended Actin Structures

Washington University, Saint Louis MO

Investigators

Abstract

0240770 Carlsson This work is aimed at clarifying the mechanisms by which cells integrate a set of external inputs to determine a motility response. Algorithms are developed for treating cross-linking and elasticity of growing actin-filament networks in the presence of several types of cross-linking proteins. These are used to determine the response of a cell to external signals that influence cross-linking and branching rates. The algorithms use a stochastic-growth methodology, which treats actin filament growth, depolymerization, capping, branch formation and detachment, and attachment of filaments to each other by cross-links. Elastic effects are included in the algorithms by the use of a special-points method. The three-dimensional structure of the actin cytoskeleton is followed at a resolution of individual subunits. The values of the rate parameters in the model are obtained from in vitro experiments for simplified cases. The code is also used to evaluate the potential for spontaneous formation of localized protrusions. The model predictions are tested by polymerization experiments with several types of cross-linking and branching proteins. Practically all types of cells are capable of moving in a way very different from muscle cells: white blood cells chasing bacteria, cells moving to remodel tissue after an injury, and migrating cancerous cells. Such motion is based on the protein actin, which is very abundant in cells, and accumulates in long filaments. These filaments can connect to each other, forming networks or other types of structures, which can push against a cell membrane and thus cause the cell to move. The "decision" about whether and how a cell moves is based on external signals, which activate or deactivate various types of filament connections. But it is not known exactly what actin structures form in response to a given set of external signals. The calculations predict these structures using powerful simulation methodologies based on parallel computers. By thus establishing the response of the actin structures in cells to external signals, one can hope to better understand the nature of diseases related to these actin structures. This will also help in understanding the migration of cancerous cells, which could eventually aid the development of cancer treatments. This grant is made under the Joint DMS/NIGMS Initiative to Support Research Grants in the Area of Mathematical Biology. This is a joint competition sponsored by the Division of Mathematical Sciences (DMS) at the National Science Foundation and the National Institute of General Medical Sciences (NIGMS) at the National Institutes of Health.