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Molecular and Cellular Biology, September 1998, p. 5148-5156, Vol. 18, No. 9
0270-7306/98/$00.00+0

Persistent Activation of Mitogen-Activated Protein Kinases p42 and p44 and ets-2 Phosphorylation in Response to Colony-Stimulating Factor 1/c-fms Signaling

Lindsay F. Fowles,1 Michele L. Martin,2 Lori Nelsen,2 Katryn J. Stacey,1 Douglas Redd,2 Ying Mei Clark,2 Yoshikune Nagamine,3 Martin McMahon,4 David A. Hume,1 and Michael C. Ostrowski2,*

Departments of Microbiology and Biochemistry and the Centre for Molecular and Cellular Biology, University of Queensland, Queensland Q4072, Australia1; Department of Molecular Genetics, Ohio State University, Columbus, Ohio 432102; Friedrich-Miescher-Institute, Basel, Switzerland3; and DNAX Research Institute, Palo Alto, California 943044

Received 22 December 1997/Returned for modification 6 March 1998/Accepted 25 June 1998

An antibody that specifically recognized phosphothreonine 72 in ets-2 was used to determine the phosphorylation status of endogenous ets-2 in response to colony-stimulating factor 1 (CSF-1)/c-fms signaling. Phosphorylation of ets-2 was detected in primary macrophages, cells that normally express c-fms, and in fibroblasts engineered to express human c-fms. In the former cells, ets-2 was a CSF-1 immediate-early response gene, and phosphorylated ets-2 was detected after 2 to 4 h, coincident with expression of ets-2 protein. In fibroblasts, ets-2 was constitutively expressed and rapidly became phosphorylated in response to CSF-1. In both cell systems, ets-2 phosphorylation was persistent, with maximal phosphorylation detected 8 to 24 h after CSF-1 stimulation, and was correlated with activation of the CSF-1 target urokinase plasminogen activator (uPA) gene. Kinase assays that used recombinant ets-2 protein as a substrate demonstrated that mitogen-activated protein (MAP) kinases p42 and p44 were constitutively activated in both cell types in response to CSF-1. Immune depletion experiments and the use of the MAP kinase kinase inhibitor PD98059 indicate that these two MAP kinases are the major ets-2 kinases activated in response to CSF-1/c-fms signaling. In the macrophage cell line RAW264, conditional expression of raf kinase induced ets-2 expression and phosphorylation, as well as uPA mRNA expression. Transient assays mapped ets/AP-1 response elements as critical for basal and CSF-1-stimulated uPA reporter gene activity. These results indicate that persistent activation of the raf/MAP kinase pathway by CSF-1 is necessary for both ets-2 expression and posttranslational activation in macrophages.

* Corresponding author. Mailing address: Department of Molecular Genetics, 484 West Twelfth Ave., The Ohio State University, Columbus, OH 43210. Phone: (614) 688-3824. Fax: (614) 292-4466. E-mail: ostrowski.4{at}osu.edu.

Molecular and Cellular Biology, September 1998, p. 5148-5156, Vol. 18, No. 9
0270-7306/98/$00.00+0


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