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PI(3)Kγ has an important context-dependent role in neutrophil chemokinesis

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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Figure 1: Polarized accumulation of PtdIns(3,4)P2 and PtdIns(3,4,5)P3 is regulated by PI(3)Kγ.
Figure 2: Neutrophil migration is regulated by PI(3)K activity.
Figure 3: Neutrophil chemokinesis is regulated by PI(3)K activity.
Figure 4: Integrin function can be regulated by PI(3)Kγ.
Figure 5: Polarization of F-actin can be regulated by PI(3)Kγ.

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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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Correspondence to Len Stephens.

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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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