Microbes seeking food and phagocytic immune cells stalking their prey rely on chemical signals, or chemoattractants, to guide their paths. Chemotactic cells can orient their anterior edge toward a stimulus gradient despite their uniform distribution of cell surface receptors. Five reports focus on the role that phosphatidylinositol 3' kinases (PI3Ks) play in chemotaxis (see the Perspective by Dekker and Segal). Hirsch et al., Li et al., and Sasaki et al. describe the phenotype of mice that lack PI3Kγ an isoform that is activated in response to G protein-coupled receptors (GPCRs). Defects in these animals show that PI3Kγ is required for a number of functions of neutrophils and T cells in vitro and in vivo. All three groups note that the inflammatory response is disrupted in several ways. Neutrophils from the mutant animals showed impaired migration and respiratory burst in response to stimulation through GPCRs. Sasaki et al. also found T cell activation through the T cell receptor was disrupted. Li et al. also generated mice lacking phospholipase C (PLC)-β 2 and PLC-β 3. They report that whereas PI3Kγ is required for normal production of immunoglobulin (Ig) containing the λ light chains, the PLC pathway can inhibit chemotaxis and production of Igλ L. The results should enhance efforts in the development of pharmaceuticals to manage inflammation. An internal signaling gradient may accommodate such the directional chemotatic response. Jin et al. show that in highly polarized amoeba cells, membrane-bound G protein subunits were present in a shallow anterior-posterior gradient. Servant et al. also determined that such an internal signal gradient involves the activities of Rho family of guanosine triphosphatases and PI3K in neutrophil-like cells. Hence, signaling molecules appear to regulate an internal gradient that determines chemotactic sensitivity.
Hirsch, E., Katanaev, V.L., Garlanda, C., Azzolino, O., Pirola, L., Silengo, L., Sozzani, S., Montovani, A., Altruda, F., and Wymann, M.P. (2000) Central role for G protein-coupled phosphoinositide 3-kinase γ in inflammation. Science 287: 1049-1053. [Abstract] [Full Text]
Li, Z., Jiang, H., Xie, W., Zhang, Z., Smrcka, A.V., and Wu., D. (2000) Roles for PLC-β2 and -β3 and PI3Kγ in chemoattractant-mediated signal transduction. Science 287: 1046-1049. [Abstract] [Full Text]
Sasaki, T., Irie-Sasaki, J., Jones, R.G., Oliveira-dos-Santos, A.J., Stanford, W.L., Bolon, B., Wakeham, A., Itie, A., Bouchard, D., Kozieradzki, I., Joza, N., Mak, T.W., Ohashi, P.S., Suzuki, A., and Penninger, J.M. (2000) Function of phosphoinositide 3-kinase γ in thymocyte development, T cell activation, and neutrophil migration. Science 287: 1040-1046. [Abstract] [Full Text]
Servant, G., Weiner, O.D., Herzmark, P., Balla, T., Sedat, J.W., and Bourne, H.R. (2000) Polarization of chemoattractant receptor signaling during neutrophil chemotaxis. Science 287: 1037-1040. [Abstract] [Full Text]