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The M-CSF receptor substrate and interacting protein FMIP is governed in its subcellular localization by protein kinase C-mediated phosphorylation, and thereby potentiates M-CSF-mediated differentiation

Oncogene volume 23, pages 6581–6589 (2004)Cite this article

Abstract

Macrophage colony-stimulating factor (M-CSF or CSF-1) and its cognate receptor, the tyrosine kinase c-fms, are essential for monocyte and macrophage development. We have recently identified an Fms-interacting protein (FMIP) that binds transiently to the cytoplasmic domain of activated Fms molecules and is phosphorylated on tyrosine by Fms tyrosine kinase. FMIP is a substrate not only for Fms but also for protein kinase C (PKC). Mutagenesis reveals that this occurs on serines 5 and 6. Adjacent to these sites is a nuclear localization signal (NLS). We show that this NLS is essential for the predominantly nuclear localization of FMIP. Generation of phosphomimetic substitutions on serine residues 5 and 6 confirms that PKC-mediated phosphorylation on this site leads to translocation of FMIP to the cytosol. Furthermore, the mutant FMIP (FMIPSS5,6AA) was detected abundantly in the nucleus even in the presence of activated PKCalpha. Wild-type FMIP and FMIPSS5,6AA inhibited M-CSF-mediated survival signaling, while FMIPSS5,6EE-expressing cells survived and differentiated into macrophages more efficiently than wild-type cells in the presence of M-CSF or TPA. We conclude M-CSF-mediated activation of PKCalpha can potentiate FMIP action to initiate survival/differentiation signaling.

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Acknowledgements

We thank Regina Wilms, Sabine Klebba-Faerber and Karsten Heidrich for technical assistance, Bruce Boschek for critically reading the manuscript, the late Heiner Niemann for encouragement to continue this work. The research was supported by Sonderforschungsbereich 566 (B2) and the Deutsche Forschungsgemeinschaft (Ta-111/8/-3).

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Authors and Affiliations

  1. Institut für Biochemie, OE 4310, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, Hannover, D-30623, Germany

    Annalisa Mancini, Alexandra Koch & Teruko Tamura

  2. Department of Biomolecular Sciences, UMIST, Manchester, M60 1QD, UK

    Anthony D Whetton

  3. Faculty of Medicine, University of Manchester, Christie Hospital, Withington, Manchester, M20 9BX, UK

    Anthony D Whetton

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  1. Annalisa Mancini
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Correspondence to Teruko Tamura.

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Mancini, A., Koch, A., Whetton, A. et al. The M-CSF receptor substrate and interacting protein FMIP is governed in its subcellular localization by protein kinase C-mediated phosphorylation, and thereby potentiates M-CSF-mediated differentiation. Oncogene 23, 6581–6589 (2004). https://doi.org/10.1038/sj.onc.1207841

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