Abstract
The directional movement of cells in a gradient of external stimulus is termed chemotaxis and is important in many aspects of development and differentiated cell function. Phophoinositide 3-kinases (PI(3)Ks) are thought to have critical roles within the gradient-sensing machinery of a variety of highly motile cells1,2, such as mammalian phagocytes3, allowing these cells to respond quickly and efficiently to shallow gradients of soluble stimuli. Our analysis of mammalian neutrophil migration towards ligands such as fMLP shows that, although PtdIns(3,4)P2 and PtdIns(3,4,5)P3 accumulate in a PI(3)Kγ-dependent fashion at the up-gradient leading-edge, this signal is not required for efficient gradient-sensing and gradient-biased movement. PI(3)Kγ activity is however, a critical determinant of the proportion of cells that can move, that is, respond chemokinetically, in reaction to fMLP. Furthermore, this dependence of chemokinesis on PI(3)Kγ activity is context dependent, both with respect to the state of priming of the neutrophils and the type of surface on which they are migrating. We propose this effect of PI(3)Kγ is through roles in the regulation of some aspects of neutrophil polarization that are relevant to movement, such as integrin-based adhesion and the accumulation of polymerized (F)-actin at the leading-edge.
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References
Ward, S. G. Do phosphoinositide 3-kinases direct lymphocyte navigation? Trends Immunol. 25, 67–74 (2004).
Manahan, C. L., Iglesias, P. A., Long, Y. & Devreotes, P. N. Chemoattractant signaling in dictyostelium discoideum. Annu. Rev. Cell Dev. Biol. 20, 223–253 (2004).
Rickert, P., Weiner, O. D., Wang, F., Bourne, H. R. & Servant, G. Leukocytes navigate by compass: roles of PI3Kγ and its lipid products. Trends Cell Biol. 10, 466–473 (2000).
Funamoto, S., Meili, R., Lee, S., Parry, L. & Firtel, R. A. Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell 109, 611–623 (2002).
Servant, G. et al. Polarization of chemoattractant receptor signaling during neutrophil chemotaxis. Science 287, 1037–1040 (2000).
Nishio, M. et al. Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIPI. Nature Cell Biol. 8, doi:10.1038/ncb1515 (2006).
Knall, C., Worthen, G. S. & Johnson, G. L. Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils independent of extracellular signal-regulated kinase and p38 mitogen-activated protein kinases. Proc. Natl Acad. Sci. USA 94, 3052–3057 (1997).
Sasaki, T. et al. Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration. Science 287, 1040–1046 (2000).
Hirsch, E. et al. Central role for G protein-coupled phosphoinositide 3-kinase γ in inflammation. Science 287, 1049–1053 (2000).
Li, Z. et al. Roles of PLC-β2 and -β3 and PI3Kγ in chemoattractant-mediated signal transduction. Science 287, 1046–1049 (2000).
Suire, S. et al. Gβγ and the Ras binding domain of p110γ are both important regulators of PI3Kγ signalling in neutrophils. Nature Cell Biol. 8, 1303–1309 (2006).
Sadhu, C., Masinovsky, B., Dick, K., Sowell, C. G. & Staunton, D. E. Essential role of phosphoinositide 3-kinase δ in neutrophil directional movement. J. Immunol. 170, 2647–2654 (2003).
Coffer, P. J. et al. Comparison of the roles of mitogen-activated protein kinase kinase and phosphatidylinositol 3-kinase signal transduction in neutrophil effector function. Biochem. J. 329, 121–130 (1998).
Hannigan, M. et al. Neutrophils lacking phosphoinositide 3-kinase γ show loss of directionality during N-formyl-Met-Leu-Phe-induced chemotaxis. Proc. Natl Acad. Sci. USA 99, 3603–3608 (2002).
Niggli, V. & Keller, H. The phosphatidylinositol 3-kinase inhibitor wortmannin markedly reduces chemotactic peptide-induced locomotion and increases in cytoskeletal actin in human neutrophils. Eur. J. Pharmacol. 335, 43–52 (1997).
Loovers, H. M. et al. Distinct roles of PI(3,4,5)P3 during chemoattractant signaling in Dictyostelium: a quantitative in vivo analysis by inhibition of PI3-kinase. Mol. Biol. Cell 17, 1503–1513 (2006).
Laudanna, C., Kim, J. Y., Constantin, G. & Butcher, E. Rapid leukocyte integrin activation by chemokines. Immunol. Rev. 186, 37–46 (2002).
Sengelov, H., Kjeldsen, L., Diamond, M. S., Springer, T. A. & Borregaard, N. Subcellular localization and dynamics of Mac-1 (αm β2) in human neutrophils. J. Clin. Invest. 92, 1467–1476 (1993).
Smith, D. F. et al. Leukocyte phosphoinositide-3 kinase γ is required for chemokine-induced, sustained adhesion under flow in vivo. J. Leukoc. Biol. DOI: 10.1189/jlb.0306227 (2006).
Niggli, V. A membrane-permeant ester of phosphatidylinositol 3,4, 5-trisphosphate (PIP(3)) is an activator of human neutrophil migration. FEBS Lett. 473, 217–221 (2000).
Sasaki, A. T. & Firtel, R. A. Finding the way: directional sensing and cell polarization through Ras signalling. Novartis Found. Symp. 269, 73–87 (2005).
Weiner, O. D. Regulation of cell polarity during eukaryotic chemotaxis: the chemotactic compass. Curr. Opin. Cell Biol. 14, 196–202 (2002).
Condliffe, A. M. et al. Sequential activation of class IB and class important for the primed respiratory burst of human but not murine neutrophils. Blood 106, 1432–1440 (2005).
Haslett, C., Guthrie, L. A., Kopaniak, M. M., Johnston, R. B., Jr. & Henson, P. M. Modulation of multiple neutrophil functions by preparative methods or trace concentrations of bacterial lipopolysaccharide. Am. J. Pathol. 119, 101–110 (1985).
Kanegasaki, S. et al. A novel optical assay system for the quantitative measurement of chemotaxis. J. Immunol. Methods 282, 1–11 (2003).
Wells, C. M. & Ridley, A. J. Analysis of cell migration using the Dunn chemotaxis chamber and time-lapse microscopy. Methods Mol. Biol. 294, 31–41 (2005).
Zicha, D., Dunn, G. & Jones, G. Analyzing chemotaxis using the Dunn direct-viewing chamber. Methods Mol. Biol. 75, 449–457 (1997).
Keller, H. & Niggli, V. Effects of cytochalasin D on shape and fluid pinocytosis in human neutrophils as related to cytoskeletal changes (actin,α-actinin and microtubules). Eur. J. Cell Biol. 66, 157–164 (1995).
Dormann, D., Libotte, T., Weijer, C. J. & Bretschneider, T. Simultaneous quantification of cell motility and protein-membrane-association using active contours. Cell Motil. Cytoskeleton 52, 221–230 (2002).
Acknowledgements
This work was funded by the Biotechnology and Biological Sciences Research Council (BBSRC). L.M. has a Cooperative Awards in Science and Engineering (CASE) studentship from Novartis and the BBSRC. S.K. is a CJ Martin Fellow of the National Health and Medical Resarch Council/National Heart Foundation of Australia (NHMRC/NHF).
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Ferguson, G., Milne, L., Kulkarni, S. et al. PI(3)Kγ has an important context-dependent role in neutrophil chemokinesis. Nat Cell Biol 9, 86–91 (2007). https://doi.org/10.1038/ncb1517
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DOI: https://doi.org/10.1038/ncb1517
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