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Differentiation

Src-family kinases play an essential role in differentiation signaling downstream of macrophage colony-stimulating factor receptors mediating persistent phosphorylation of phospholipase C-γ2 and MAP kinases ERK1 and ERK2

Leukemia volume 22, pages 161–169 (2008)Cite this article

Abstract

Macrophage colony-stimulating factor (M-CSF) has been found to be involved in multiple developmental processes, especially production of cells belonging to the mononuclear phagocyte system. The decision of myeloid progenitor cells to commit to differentiation depends on activation levels of the mitogen-activated protein kinases (MAPK), ERK1 and ERK2. Using the murine myeloid progenitor cell line FD-Fms, we show here that persistent activity of Src-family kinases (SFK) is necessary for FD-Fms cell differentiation to macrophages in response to M-CSF. Chemical inhibition of SFK blocked FD-Fms cell differentiation while it caused strong inhibition of the late phosphorylation of phospholipase C (PLC)-γ2 and MAPK. The PLC inhibitor U73122, previously shown to block M-CSF-induced differentiation, strongly decreased long-term MAPK phosphorylation. Interestingly, inhibiting SFK with SU6656 or the MAPK kinases MEK with U0126 significantly impaired development of mononuclear phagocytes in cultures of mouse bone marrow cells stimulated with M-CSF. Collectively, results support a model in which SFK are required for sustained PLC activity and MAPK activation above threshold required for commitment of myeloid progenitors to macrophage differentiation.

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Acknowledgements

This work was supported by grants from the Ligue Nationale Contre le Cancer (Equipe labellisée 2000 and 2004), Association pour la Recherche contre le Cancer (grant no 4000) and the Centre National de la Recherche Scientifique. CB-H and JT were supported by fellowships from French Ministére de la Recherche.

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Author notes

  1. C Bourgin-Hierle

    Present address: 3Current address: The Burnham Institute for Medical Research, Pathology Department, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA,

  2. C Bourgin-Hierle and S Gobert-Gosse: These authors contributed equally to this work

Authors and Affiliations

  1. Centre de Génétique Moléculaire et Cellulaire, Université de Lyon, UMR 5534, Université Claude Bernard Lyon 1, CNRS, Villeurbanne, France

    C Bourgin-Hierle, S Gobert-Gosse, J Thérier, M-F Grasset & G Mouchiroud

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  1. C Bourgin-Hierle
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Correspondence to G Mouchiroud.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Bourgin-Hierle, C., Gobert-Gosse, S., Thérier, J. et al. Src-family kinases play an essential role in differentiation signaling downstream of macrophage colony-stimulating factor receptors mediating persistent phosphorylation of phospholipase C-γ2 and MAP kinases ERK1 and ERK2. Leukemia 22, 161–169 (2008). https://doi.org/10.1038/sj.leu.2404986

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