The role of phosphoinositide-regulated actin reorganization in chemotaxis and cell migration

Abstract

Reorganization of the actin cytoskeleton is essential for cell motility and chemotaxis. Actin-binding proteins (ABPs) and membrane lipids, especially phosphoinositides PI(4,5)P2 and PI(3,4,5)P3 are involved in the regulation of this reorganization. At least 15 ABPs have been reported to interact with, or regulated by phosphoinositides (PIPs) whose synthesis is regulated by extracellular signals. Recent studies have uncovered several parallel intracellular signalling pathways that crosstalk in chemotaxing cells. Here, we review the roles of ABPs and phosphoinositides in chemotaxis and cell migration.

Linked articles: This article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-24.

Figure 1

Reactions catalyzed by PI3K and PTEN. PI3K phosphorylates the D3 position of phosphatidylinositol (PI), PI4P or PI(4,5)P₂ to produce PI3P, PI(3,4)P₂ or PI(3,4,5)P₃ respectively. PTEN has been shown to dephosphorylate the D3 position of both PI(3,4,5)P₃ and PI(3,4)P₂ and thus to reverse the reactions catalyzed by PI3K.

Figure 2

Functional role of PI3K and PTEN in chemotaxis. (A) Spatial-temporal regulation of PTEN and PI3K induces cell polarization in response to a chemoattractant signal. When cells sense the chemoattractant signal, a signalling pathway yet to be identified promotes the rapid translocation of PI3K to the leading edge facing the higher chemoattractant concentration and the delocalization of PTEN from the leading edge. Therefore, PI(3,4,5)P₃ is synthesized from PI(4,5)P₂ at the leading edge and prevented from accumulating on the sides and at the back of the cell by PTEN, causing a very steep anterior/posterior PI(3,4,5)P₃ gradient. (B) Chemotaxis signal pathway in Dictyostelium and neutrophils. Binding of chemoattractant to G-protein coupled receptors releases the Gα heterodimer from the heterotrimeric Gα proteins. Dissociated Gα proteins stimulate PI(3,4,5)P₃ production via PI3K and lead to membrane translocation of PI(3,4,5)P₃-binding ABPs, probably the members of myosin I. Finally, there is remodelling of the actin cytoskeleton at the leading edge required for the formation of novel cell protrusions.

Figure 3

Activation of actin filament assembly by PI(3,4,5)P₃ through Rho GTPase. In neutrophils, Rho family guanine nucleotide exchange factors (GEFs) are PI3K effectors, which lead to the accumulation of activated Rac (Rac-GTP). The feedback loop required for the amplification of the pathway may involve actin polymerization.

Figure 4

Regulation of ABPs by PI(4,5)P₂. (A) The activation of ERM proteins is mediated by both exposure to PI(4,5)P₂ and phosphorylation of the C-terminal threonine. The C-terminal residue of activated ERM proteins binds to F-actin filaments. (B) Integrins can bind directly to the talin head domain. Through its tail domain, talin can bind directly to actin as well as to other components of the linkage, such as vinculin. (C) PI(4,5)P₂ activates WASP and induces WASP dimerization. The Arp2/3 complex mediates actin branch formation activated by WASP dimers on the inside surface of a cell membrane. (D) In the inactive state, cofilin is bound to PI(4,5)P₂ at the plasma membrane through its Asp¹²² residue. Release of cofilin from PI(4,5)P₂ at the plasma membrane increases severing of actin filaments, generating free barbed ends that define the sites of dendritic nucleation by the Arp2/3 complex. (E) PI(4,5)P₂ sequesters gelsolin and increases actin polymerization.