A PtdInsP(3)- and Rho GTPase-mediated positive feedback loop regulates neutrophil polarity.
When presented with a gradient of chemoattractant, many eukaryotic cells respond with polarized accumulation of the phospholipid PtdIns(3,4,5)P(3). This lipid asymmetry is one of the earliest readouts of polarity in neutrophils, Dictyostelium discoideum and fibroblasts. However, the mechanisms that regulate PtdInsP(3) polarization are not well understood. Using a cationic lipid shuttling system, we have delivered exogenous PtdInsP(3) to neutrophils. Exogenous PtdInsP(3) elicits accumulation of endogenous PtdInsP(3) in a positive feedback loop that requires endogenous phosphatidylinositol-3-OH kinases (PI(3)Ks) and Rho family GTPases. This feedback loop is important for establishing PtdInsP(3) polarity in response to both chemoattractant and to exogenous PtdInsP(3); it may function through a self-organizing pattern formation system. Emergent properties of positive and negative regulatory links between PtdInsP(3) and Rho family GTPases may constitute a broadly conserved module for the establishment of cell polarity during eukaryotic chemotaxis.
Weiner
Orion D
OD
Department of Cell Biology, Harvard Medical School and Beth Israel Deaconess Medical Center, 240 Longwood Ave/ C-1, Boston, MA 02115, USA.
Neilsen
Paul O
PO
Prestwich
Glenn D
GD
Kirschner
Marc W
MW
Cantley
Lewis C
LC
Bourne
Henry R
HR
D000818:Animals; D016764:Cell Polarity / Q000502:physiology*; D002633:Chemotaxis; D004023:Dictyostelium / Q000166:cytology; D025461:Feedback, Physiological / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology; D018922:HL-60 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D009504:Neutrophils / Q000166:cytology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000502:physiology*
D006657:Histones; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; D020741:rho GTP-Binding Proteins