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Molecular and Cellular Biology, November 1999, p. 7436-7446, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Targeted Disruption of the Murine fps/fes Proto-Oncogene Reveals that Fps/Fes Kinase Activity Is Dispensable for Hematopoiesis

Yotis Senis,1 Ralph Zirngibl,2 Jennifer McVeigh,1 Andre Haman,3 Trang Hoang,3 and Peter A. Greer1,2,*

Department of Pathology1 and Department of Biochemistry,2 Cancer Research Laboratories, Queen's University, Kingston, Ontario K7L 3N6, and Laboratory of Hemopoiesis and Leukemia, Institut de Recherches Cliniques de Montreal, Montreal, Quebec H2W 1R7,3 Canada

Received 2 August 1999/Accepted 5 August 1999

The fps/fes proto-oncogene encodes a cytoplasmic protein-tyrosine kinase that is functionally implicated in the survival and terminal differentiation of myeloid progenitors and in signaling from several members of the cytokine receptor superfamily. To gain further insight into the physiological function of fps/fes, we targeted the mouse locus with a kinase-inactivating missense mutation. Mutant Fps/Fes protein was expressed at normal levels in these mice, but it lacked detectable kinase activity. Homozygous mutant animals were viable and fertile, and they showed no obvious defects. Flow cytometry analysis of bone marrow showed no statistically significant differences in the levels of myeloid, erythroid, or B-cell precursors. Subtle abnormalities observed in mutant mice included slightly elevated total leukocyte counts and splenomegaly. In bone marrow hematopoietic progenitor cell colony-forming assays, mutant mice gave slightly elevated numbers and variable sizes of CFU-granulocyte macrophage in response to interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Tyrosine phosphorylation of Stat3 and Stat5A in bone marrow-derived macrophages was dramatically reduced in response to GM-CSF but not to IL-3 or IL-6. This suggests a distinct nonredundant role for Fps/Fes in signaling from the GM-CSF receptor that does not extend to the closely related IL-3 receptor. Lipopolysaccharide-induced Erk1/2 activation was also reduced in mutant macrophages. These subtle molecular phenotypes suggest a possible nonredundant role for Fps/Fes in myelopoiesis and immune responses.

* Corresponding author. Mailing address: Cancer Research Laboratories, Departments of Pathology and Biochemistry, Department of Biochemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada. Phone: (613) 533-2813. Fax: (613) 533-6830. E-mail: greerp{at}post.queensu.ca.

Molecular and Cellular Biology, November 1999, p. 7436-7446, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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