Sci. STKE, 16 September 2003
CHEMOTAXIS Competition at the Leading Edge
Dictyostelium discoideum amoebae respond to the chemoattractant adenosine 3',5'-monophosphate (cAMP) by aggregating to form a multicellular organism. By activating a heterotrimeric GTP-binding protein (G protein)-coupled receptor, cAMP initiates a signaling cascade that coordinately regulates phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphatase. The result is localized accumulation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) at the cell's leading edge. Proteins harboring a pleckstrin homology (PH) domain that bind to PIP3 translocate to this region, propagating further downstream signaling that leads to chemotaxis. Luo et al. report that the inositol pyrophosphate InsP7 competes with PIP3 for binding PH domain-containing proteins. Exposure of D. discoideum cells to cAMP caused a rapid increase in InsP7. Deleting the InsP6 kinase, the enzyme that generates InsP7, resulted in a more rapid aggregation response, indicating increased sensitivity to cAMP. Increased translocation of a fluorescently labeled PH domain to the leading edge of chemotaxing cells corresponded with this increased sensitivity. No increase in PIP3 was detected. InsP7 also associated with PH domains in vitro and in vivo and inhibited PH domain interaction with PIP3. The study suggests that InsP7 controls the translocation of PH domain-containing proteins and thus can suppress chemotactic responsiveness.
H. R. Luo, Y. E. Huang, J. C. Chen, A. Saiardi, M. Iijima, K. Ye, Y. Huang, E. Nagata, P. Devreotes, S. H. Solomon, Inositol pyrophosphates mediate chemotaxis in Dictyostelium via pleckstrin homology domain-PtdIns(3,4,5)P3 interactions. Cell 114, 559-572 (2003). [Online Journal]
Citation: Competition at the Leading Edge. Sci. STKE 2003, tw360 (2003).
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