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  • Title: Akt isoforms differentially regulate neutrophil functions.
    Author: Chen J, Tang H, Hay N, Xu J, Ye RD.
    Journal: Blood; 2010 May 27; 115(21):4237-46. PubMed ID: 20332370.
    Abstract:
    In neutrophils, the phosphoinositide 3-kinase/Akt signaling cascade is involved in migration, degranulation, and O(2)(-) production. However, it is unclear whether the Akt kinase isoforms have distinct functions in neutrophil activation. Here we report functional differences between the 2 major Akt isoforms in neutrophil activation on the basis of studies in which we used individual Akt1 and Akt2 knockout mice. Akt2(-/-) neutrophils exhibited decreased cell migration, granule enzyme release, and O(2)(-) production compared with wild-type and Akt1(-/-) neutrophils. Surprisingly, Akt2 deficiency and pharmacologic inhibition of Akt also abrogated phorbol ester-induced O(2)(-) production, which was unaffected by treatment with the phosphoinositide 3-kinase inhibitor LY294002. The decreased O(2)(-) production in Akt2(-/-) neutrophils was accompanied by reduced p47(phox) phosphorylation and its membrane translocation, suggesting that Akt2 is important for the assembly of phagocyte nicotinamide adenine dinucleotide phosphate oxidase. In wild-type neutrophils, Akt2 but not Akt1 translocated to plasma membrane upon chemoattractant stimulation and to the leading edge in polarized neutrophils. In the absence of Akt2, chemoattractant-induced Akt protein phosphorylation was significantly reduced. These results demonstrate a predominant role of Akt2 in regulating neutrophil functions and provide evidence for differential activation of the 2 Akt isoforms in neutrophils.
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