Phosphoinositides and Rho proteins spatially regulate actin polymerization to initiate and maintain directed movement in a 1D model of a motile cell

¹ University of British Columbia

^* To whom correspondence should be addressed. E-mail: atdawes{at}math.ubc.ca.

Submitted on June 2, 2006
Revised on July 25, 2006
Accepted on 2 October 2006

	Abstract

Gradient sensing, polarization, and chemotaxis of motile cells involves the actin cytoskeleton, and regulatory modules, including the phosphoinositides (PIs), their kinases/phosphatases, and small GTPases (Rho proteins). Here we model their individual components (PIP, PIP₂, PIP₃; PTEN, PI3K, PI5K; Cdc42, Rac, Rho; Arp2/3, and actin), their interconversions, interactions, and modular functions in the context of a 1D dynamic model for protrusive cell motility, with parameter values derived from in vitro and in vivo studies. In response to a spatially graded stimulus, the model produces stable amplified internal profiles of regulatory components, and initiates persistent motility (consistent with experimental observations). By connecting the modules, we find that Rho GTPases work as a spatial switch, and that PIs filter noise, and define the front vs. back. Relatively fast PI diffusion also leads to selection of a unique pattern of Rho distribution from a collection of possible patterns. We use the model to explore the importance of specific hypothesized interactions, to explore mutant phenotypes, and to study the role of actin polymerization in the maintenance of the PI asymmetry. We also suggest a mechanism to explain the spatial exclusion of Cdc42 and PTEN and the inability of cells lacking active Cdc42 to properly detect chemoattractant gradients.

Key Words: Actin filaments, Cell motility, Gradient sensing, Mathematical model, Phosphoinositides, Rho proteins