Chemotactic cells can detect and move toward a shallow gradient of chemoattractant. This directional movement involves the localized synthesis of membrane lipids, specifically phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is formed in response to recruitment of phosphoinositide 3-kinase (PI3K) at the site of receptor activation. PIP3 is in turn metabolized to PIP2 by the phosphatase PTEN. Gamba et al. performed a stochastic simulation with four components: (i) binding of PI3K to activated receptors, (ii) binding of PTEN to PIP2, (iii) catalytic activity of PI3K and PTEN, and (iv) diffusion of phosphoinositides in the membrane. The model detected phase separation of the phosphoinositides PIP2 and PIP3 within the membrane. When a uniform stimulus was applied, the phosphoinositides slowly separated into PIP2-rich and PIP3-rich phases, and the rate of separation was dependent on the concentration of activated receptors and the diffusion of the lipids. When a shallow gradient (5% gradient of activated receptors over the length of the simulated membrane) of stimulus was applied, a much more rapid separation of the lipids was observed, and the PIP3-rich phase accumulated on the side with the higher concentration of activated receptors. The authors state that the results can be explained by the selective recruitment of PTEN to its product PIP2, which serves as a positive feedback mechanism that drives the system toward phase separation. The net effect is amplification of a shallow signal.
A. Gamba, A. de Candia, S. Di Talila, A. Coniglio, F. Bussolino, G. Serini, Diffusion-limited phase separation in eukaryotic chemotaxis. Proc. Natl. Acad. Sci. U.S.A. 102, 16927-16932 (2005). [Abstract] [Full Text]