Gradient Amplification

During chemotaxis, cells can sense remarkably shallow gradients in the concentration of chemoattractants that may differ by only a few percent from one end of the cell to the other. Chemoattractant receptors and their associated G proteins appear to remain evenly distributed in responding cells. However, some signaling proteins do accumulate at the leading edge of migrating cells in a manner dependent on their pleckstrin homology (PH) domains. PH domains bind to 3-phosphoinositides, so Funamoto et al. and Iijima and Devreotes have now used Dictyostelium cells to assess the distribution of phosphatidylinositol 3-kinase (PI3K) and the phosphatidylinositol-3-phosphatase PTEN, which control synthesis and degradation of the 3-phosphoinositides. Funamoto et al. found that PI3Ks tagged with green fluorescent protein were localized to the leading edge of cells exposed to a chemoattractant gradient. Both groups report that fluorescently tagged PTEN undergoes a reciprocal localization: it is lost from the leading edge and increases in concentration at the sides and rear of the cell. Loss of PTEN caused prolonged and broader spatial distribution of PH domain binding across the leading edge of the cell. Iijima and Devreotes showed that a putative binding domain for phophatidylinositol 4,5-bisphosphate [PI(4,5)P2] on PTEN is required for its localization and function. They propose that loss of PI(4,5)P2 as it becomes phosphorylated by PI3K at the leading edge of the cell may contribute to an amplification loop that leads to loss of PTEN from the membrane. The initial signal that leads to differential localization of PI3K is still not known, but localization of PI3K and PTEN and feedback regulation of PTEN appear to contribute to amplification of the chemoattractant gradient. S. Funamoto, R. Meili, S. Lee, L. Parry, R. A. Firtel, Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell 109, 611-623 (2002). [Online Journal] M. Iijima, P. Devreotes, Tumor suppressor PTEN mediates sensing of chemoattractant gradients. Cell 109, 599-610 (2002). [Online Journal]