Chemotaxis: signalling the way forward

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Abstract
Motile eukaryotic cells such as Dictyostelium discoideum and human neutrophils extend pseudopodia with a typical 1-minute life cycle. In a uniform gradient of chemoattractant, these pseudopodia are formed in random directions. During chemotaxis in a gradient of chemoattractant, the spatial and temporal aspects of the chemoattractant concentration are processed, leading to pseudopod extension at the leading edge, retraction of the uropod at the back of the cell, and suppression of lateral pseudopodia. The chemoattractant binds to seven-transmembrane-spanning serpentine receptors, and activates heterotrimeric G-proteins and small GTP-binding proteins of the Rho/Rac class, which leads to the activation of phosphatidylinositol 3-kinase (PI3K) and guanylyl cyclase. At the leading edge Rho/Rac proteins are activated. Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) accumulates here as a result of the activity of PI3K that translocates from the cytosol, whereas the PtdIns(3,4,5)P3-degrading enzyme PTEN (phosphatase and tensin homologue) dissociates from the membrane at the leading edge. Rho/Rac proteins and PtdIns(3,4,5)P3-binding proteins induce actin polymerization and pseudopod formation. At the sides and the back of the cell, myosin filaments are formed, which generate the power to retract the uropod, and also inhibit the formation of pseudopodia at the sides of the cell. In D. discoideum this is mediated predominantly by cyclic GMP, whereas in neutrophils, a Rho kinase induces myosin filaments.