PIP3, PIP2, and cell movement--similar messages, different meanings?

Abstract

The inositol lipids PI(4,5)P(2) and PI(3,4,5)P(3) are important regulators of actin polymerization, but their different temporal and spatial dynamics suggest that they perform separate roles. PI(3,4,5)P(3) seems to act as an instructive second messenger, inducing local actin polymerization. PI(4,5)P(2) appears to be present at too high a concentration and homogeneous a distribution to fulfil a similar role. Instead, we suggest that PI(4,5)P(2) acts permissively, restricting new actin polymerization to the region of the plasma membrane.

Figure 1

Temporal and Spatial Changes in PI(4,5)P₂, PI(3,4,5)P₃, and Actin Polymerization (A) Time course of changes in PI(4,5)P₂, PI(3,4,5)P₃, and actin polymerization in fMLP-stimulated neutrophils. PI(4,5)P₂, PI(3,4,5)P₃ data refer to the approximate plasma membrane concentrations. PI(3,4,5)P₃ and new actin nucleation behave similarly, but PI(4,5)P₂ levels decrease (adapted from Stephens et al., 1991, 1993; Carson et al., 1986). This response is representative of many cell types. (B) Spatial distribution of PI(4,5)P₂, PI(3,4,5)P₃, and actin polymerization in cells before stimulation and during chemotaxis, as revealed by GFP-tagged PH domains and phalloidin. Prior to stimulation, PI(4,5)P₂ and F-actin are uniformly distributed throughout the cortex with undetectable PI(3,4,5)P₃. After stimulation, PI(4,5)P₂ remains uniformly distributed, but actin and PI(3,4,5)P₃ accumulate at the leading edge of the cell (reviewed in Rickert et al., 2000).

Figure 2

Potential Molecular Targets of PI(4,5)P₂ at the Plasma Membrane (A) Local inactivation of capping proteins. Actin filaments which extend toward the cell body are capped by various F-actin capping proteins. Immediately below the membrane these proteins are inactivated by binding to PI(4,5)P₂. (B) Local activation of WASP family proteins. Binding of WASP family proteins, in concert with the Arp2/3 complex, to existing filaments is required for new filament branching. WASP can only be activated by PI(4,5)P₂ when it is bound to the plasma membrane. This ensures that newly nucleated filaments are always oriented toward the membrane and away from the cell body.