Mechanisms of Eukaryotic Chemotaxis

Chemotaxis is a fundamental cellular response that plays a central role in health and disease. Experiments in amoebae and neutrophils have shown that local accumulations of PI(3,4,5)P3 mediate the ability of cells to migrate directionally. Random pseudopod extension, phagocytosis and other spontaneous events also lead to PI(3,4,5)P3 synthesis and mark the sites of new actin filled projections. During directional sensing, it is a discreet step in the signaling pathway, downstream of G protein activation but upstream of the accumulation of PI(3,4,5)P3, that sets up the initial asymmetry. The enzymes PI3K and PTEN that regulate the local levels of the PI(3,4,5)P3 move to the anterior and posterior of the cell. Quantitative measurements have shown that the localization is dependent on the relative chemo-attractant gradient, and the final distribution of PI(3,4,5)P3 is amplified, even without the presence of an actin cytoskeleton. Multi-stimulus inputs on latrunculin treated cells can lead to bimodal responses, which can be extinguished and redistributed by shifting the concentration gradients. These observations suggest that a local excitation-global inhibition model can account for the localization of PI3K and PTEN and thereby explain directional sensing.