Activation of Rac2 and Cdc42 on Fc and complement receptor ligation in human neutrophils.
Phagocytosis is a complex process engaging a concerted action of signal-transduction cascades that leads to ingestion, subsequent phagolysosome fusion, and oxidative activation. We have previously shown that in human neutrophils, C3bi-mediated phagocytosis elicits a significant oxidative response, suggesting that activation of the small GTPase Rac is involved in this process. This is contradictory to macrophages, where only Fc receptor for immunoglobulin G (FcgammaR)-mediated activation is Rac-dependent. The present study shows that engagement of the complement receptor 3 (CR3) and FcgammaR and CR3- and FcgammaR-mediated phagocytosis activates Rac, as well as Cdc42. Furthermore, following receptor-engagement of the CR3 or FcgammaRs, a downstream target of these small GTPases, p21-activated kinase, becomes phosphorylated, and Rac2 is translocated to the membrane fraction. Using the methyltransferase inhibitors N-acetyl-S-farnesyl-L-cysteine and N-acetyl-S-geranylgeranyl-L-cysteine, we found that the phagocytic uptake of bacteria was not Rac2- or Cdc42-dependent, whereas the oxidative activation was decreased. In conclusion, our results indicate that in neutrophils, Rac2 and Cdc42 are involved in FcR- and CR3-induced activation and for properly functioning signal transduction involved in the generation of oxygen radicals.
Forsberg
Maria
M
Department of Cell Biology, Faculty of Health Sciences, Linköping University, Sweden.
Druid
Pia
P
Zheng
Limin
L
Stendahl
Olle
O
Särndahl
Eva
E
D004789:Enzyme Activation; D006801:Humans; D016177:Macrophage-1 Antigen / Q000502:physiology*; D019255:NADPH Oxidases / Q000378:metabolism; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*; D010587:Phagocytosis; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D017452:Receptors, IgG / Q000502:physiology*; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins / Q000502:physiology*; D000097766:RAC2 GTP-Binding Protein
D016177:Macrophage-1 Antigen; D019255:NADPH Oxidases; D017346:Protein Serine-Threonine Kinases; D017452:Receptors, IgG; D020764:cdc42 GTP-Binding Protein; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein