Targeted disruption of the murine fps/fes proto-oncogene reveals that Fps/Fes kinase activity is dispensable for hematopoiesis

The fps/fes proto-oncogene encodes a cytoplasmic protein-tyrosine kinase th at is functionally implicated in the survival and terminal differentiation of myeloid progenitors and in signaling from several members of the cytokin e receptor superfamily. To gain further insight into the physiological func tion of fps/fes, we targeted the mouse locus with a kinase-inactivating mis sense mutation, Mutant Fps/Fes protein was expressed at normal levels in th ese mice, but it lacked detectable kinase activity. Homozygous mutant anima ls were viable and fertile, and they showed no obvious defects. Flow cytome try analysis of bone marrow showed no statistically significant differences in the levels of myeloid, erythroid, or B-cell precursors. Subtle abnormal ities observed in mutant mice included slightly elevated total leukocyte co unts and splenomegaly. In bone marrow hematopoietic progenitor cell colony- forming assays, mutant mice gave slightly elevated numbers and variable siz es of CFU-granulocyte macrophage in response to interleukin-3 (IL-3) and gr anulocyte-macrophage colony-stimulating factor (GM-CSF). Tyrosine phosphory lation of Stat3 and Stat5A in bone marrow-derived macrophages was dramatica lly 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 recepto r that does not extend to the closely related IL-3 receptor. Lipopolysaccha ride-induced Erk1/2 activation was also reduced in mutant macrophages. Thes e subtle molecular phenotypes suggest a possible nonredundant role for Fps/ Fes in myelopoiesis and immune responses.