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J. Biol. Chem., Vol. 282, Issue 26, 18980-18990, June 29, 2007

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c-Fms Tyrosine 559 Is a Major Mediator of M-CSF-induced Proliferation of Primary Macrophages^*

Sunao Takeshita, Roberta Faccio^¶, Jean Chappel, Ling Zheng, Xu Feng^||, Jason D. Weber^**, Steven L. Teitelbaum, and F. Patrick Ross¹

From the Departments of Pathology and Immunology, ^¶Orthopaedic Surgery, and ^**Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, Department of Bone and Joint Disease, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi 474-8522, Japan, and ^||Department of Pathology, University of Alabama, Birmingham, Alabama 35294

The molecular mechanisms by which binding of monocyte/macrophage colony-stimulating factor to its receptor c-Fms promotes replication in primary macrophages are incompletely understood, as all previous studies involved overexpression of receptor mutants in transformed cells not endogenously expressing the receptor. To address this issue we retrovirally expressed, in bone marrow-derived macrophages, a chimeric receptor containing a range of tyrosine to phenylalanine mutations in the c-Fms cytoplasmic tail. We measured incorporation of bromodeoxyuridine as a marker of proliferation and phosphorylation of ERKs, Akt, and the receptor itself. Our data indicate that tyrosine 559 is the major mediator of receptor activation and cell death, intracellular signaling, and cell proliferation and that the tyrosine residues at positions 697 and 807 play lesser roles in these events. Importantly, we find that activation of the ERK and Akt pathways is necessary but not sufficient for induction of macrophage proliferation. Using specific small molecule inhibitors we find that a combination of the Src family kinase, phosphatidylinositol 3-kinase/Akt, phospholipase C, and ERK pathways mediates macrophage proliferation in response to M-CSF.

Received for publication, November 28, 2006 , and in revised form, April 9, 2007.

^* This work was supported by National Institutes of Health Grants AR46852 and AR48812 (to F. P. R.) and AR32788, AR46523, and AR48853 (to S. L. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Washington University School of Medicine, Dept. of Pathology and Immunology, Campus Box 8118, 660 South Euclid Ave., St. Louis, MO 63110. Tel.: 314-454-8079; Fax: 314-454-5505; E-mail: rossf{at}wustl.edu.

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