Colony-stimulating factor-1-induced oscillations in phosphatidylinositol-3 kinase/AKT are required for caspase activation in monocytes undergoing differentiation into macrophages

Arnaud Jacquel, Naïma Benikhlef, Jérôme Paggetti, Najoua Lalaoui, Leslie Guery, Erick K. Dufour, Marion Ciudad, Cindy Racoeur, Olivier Micheau, Laurent Delva, Nathalie Droin, Eric Solary*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

51 Citations (Scopus)

Abstract

The differentiation of human peripheral blood monocytes into resident macrophages is driven by colony-stimulating factor-1 (CSF-1), which upon interaction with CSF-1 receptor (CSF-1R) induces within minutes the phosphorylation of its cytoplasmic tyrosine residues and the activation of multiple signaling complexes. Caspase-8 and -3 are activated at day 2 to 3 and contribute to macrophage differentiation, for example, through cleavage of nucleophosmin. Here, we show that the phosphatidylinositol-3 kinase and the downstream serine/threonine kinase AKT connect CSF-1R activation to caspase-8 cleavage. Most importantly, we demonstrate that successive waves ofAKT activation with increasing amplitude and duration are required to provoke the formation of the caspase-8-activating molecular platform. CSF-1 and its receptor are both required for oscillations in AKT activation to occur, and expression of a constitutively active AKT mutant prevents the macrophage differentiation process. The extracellular receptor kinase 1/2 pathway is activated with a coordinated oscillatory kinetics in a CSF-1R-dependent manner but plays an accessory role in caspase activation and nucleophosmin cleavage. Altogether, CSF-1 stimulation activates a molecular clock that involves phosphatidylinositol-3 kinase and AKT to promote caspase activation. This oscillatory signaling pathway, which is coordinated with extracellular receptor kinase 1/2 oscillatory activation, involves CSF-1 and CSF-1R and controls the terminal differentiation of macrophages.

Original languageEnglish
Pages (from-to)3633-3641
Number of pages9
JournalUnknown Journal
Volume114
Issue number17
DOIs
Publication statusPublished - 2009
Externally publishedYes

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