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Blood, 22 October 2009, Vol. 114, No. 17, pp. 3633-3641. Prepublished online as a Blood First Edition Paper on August 31, 2009; DOI 10.1182/blood-2009-03-208843. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-03-208843v1 114/17/3633    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Jacquel, A. Articles by Solary, E. PubMed PubMed Citation Articles by Jacquel, A. Articles by Solary, E. Related Collections Phagocytes, Granulocytes, and Myelopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS Colony-stimulating factor-1–induced oscillations in phosphatidylinositol-3 kinase/AKT are required for caspase activation in monocytes undergoing differentiation into macrophages Arnaud Jacquel1,2, Naïma Benikhlef1,2, Jérôme Paggetti1,2, Najoua Lalaoui1,2, Leslie Guery1,2, Erick K. Dufour1,2, Marion Ciudad1,2, Cindy Racoeur1,2, Olivier Micheau1,2, Laurent Delva1,2, Nathalie Droin1,2, and Eric Solary13 1 Faculty of Medicine, Inserm UMR866, Dijon; 2 Faculty of Medicine, University of Burgundy, Dijon; and 3 Centre Hospitalier Universitaire (CHU) Le Bocage, Dijon, France 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 of AKT 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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