PI(3)Kgamma has an important context-dependent role in neutrophil chemokinesis.
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 cells, such as mammalian phagocytes, 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)P(2) and PtdIns(3,4,5)P(3) accumulate in a PI(3)Kgamma-dependent fashion at the up-gradient leading-edge, this signal is not required for efficient gradient-sensing and gradient-biased movement. PI(3)Kgamma 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)Kgamma 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)Kgamma 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.
Ferguson
G John
GJ
The Babraham Institute, Cambridge, CB22 3AT, UK.
Milne
Laura
L
Kulkarni
Suhasini
S
Sasaki
Takehiko
T
Walker
Simon
S
Andrews
Simon
S
Crabbe
Tom
T
Finan
Peter
P
Jones
Gareth
G
Jackson
Shaun
S
Camps
Montserrat
M
Rommel
Christian
C
Wymann
Matthias
M
Hirsch
Emilio
E
Hawkins
Phillip
P
Stephens
Len
L
D000199:Actins / Q000737:chemistry; D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016023:Integrins / Q000502:physiology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*
D000199:Actins; D016023:Integrins; D007527:Isoenzymes; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; C060980:phosphatidylinositol 3,4-diphosphate; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse