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Molecular and Cellular Biology, November 2000, p. 8026-8034, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

ets-2 Is a Target for an Akt (Protein Kinase B)/Jun N-Terminal Kinase Signaling Pathway in Macrophages of motheaten-viable Mutant Mice

James L. Smith,1 Alicia E. Schaffner,1 Joseph K. Hofmeister,1,2 Matthew Hartman,1 Guo Wei,1 David Forsthoefel,1 David A. Hume,3 and Michael C. Ostrowski1,*

Department of Molecular Genetics and the Comprehensive Cancer Center1 and Division of Hematology & Oncology,2 Ohio State University, Columbus, Ohio 43210, and Departments of Biochemistry and Microbiology and Centre for Molecular and Cellular Biology, University of Queensland, Brisbane, Australia3

Received 20 March 2000/Returned for modification 4 May 2000/Accepted 8 August 2000

The transcription factor ets-2 was phosphorylated at residue threonine 72 in a colony-stimulating factor 1 (CSF-1)- and mitogen-activated protein kinase-independent manner in macrophages isolated from motheaten-viable (me-v) mice. The CSF-1 and ets-2 target genes coding for Bcl-x, urokinase plasminogen activator, and scavenger receptor were also expressed at high levels independent of CSF-1 addition to me-v cells. Akt (protein kinase B) was constitutively active in me-v macrophages, and an Akt immunoprecipitate catalyzed phosphorylation of ets-2 at threonine 72. The p54 isoform of c-jun N-terminal kinase-stress-activated kinase (JNK- SAPK) coimmunoprecipitated with Akt from me-v macrophages, and treatment of me-v cells with the specific phosphatidylinositol 3-kinase inhibitor LY294002 decreased cell survival, Akt and JNK kinase activities, ets-2 phosphorylation, and Bcl-x mRNA expression. Therefore, ets-2 is a target for phosphatidylinositol 3-kinase-Akt-JNK action, and the JNK p54 isoform is an ets-2 kinase in macrophages. Constitutive ets-2 activity may contribute to the pathology of me-v mice by increasing expression of genes like the Bcl-x gene that promote macrophage survival.

* Corresponding author. Mailing address: Department of Molecular Genetics, Ohio State University, 484 W. 12th Ave., Columbus, OH 43210. Phone: (614) 688-3824. Fax: (614) 688-8727. E-mail: ostrowski.4{at}osu.edu.

Molecular and Cellular Biology, November 2000, p. 8026-8034, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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