title: Activated Fps/Fes tyrosine kinase regulates erythroid differentiation and survival.
abstract: OBJECTIVE
  A substantial body of evidence implicates the cytoplasmic protein tyrosine kinase Fps/Fes in regulation of myeloid differentiation and survival. In this study we wished to determine if Fps/Fes also plays a role in the regulation of erythropoiesis.
  
  
  METHODS
  Mice tissue-specifically expressing a "gain-of-function" mutant fps/fes transgene (fps(MF)) encoding an activated variant of Fps/Fes (MFps), were used to explore the in vivo biological role of Fps/Fes. Erythropoiesis in these mice was assessed by hematological analysis, lineage marker analysis, bone-marrow colony assays, and biochemical approaches.
  
  
  RESULTS
  fps(MF) mice displayed reductions in peripheral red cell counts. However, there was an accumulation of immature erythroid precursors, which displayed increased survival. Fps/Fes and the related Fer kinase were both detected in early erythroid progenitors/blasts and in mature red cells. Fps/Fes was also activated in response to erythropoietin (EPO) and stem cell factor (SCF), two critical factors in erythroid development. In addition, increased Stat5A/B activation and reduced Erk1/2 phosphorylation was observed in fps(MF) primary erythroid cells in response to EPO or SCF, respectively.
  
  
  CONCLUSIONS
  These data support a role for Fps/Fes in regulating the survival and differentiation of erythroid cells through modulation of Stat5A/B and Erk kinase pathways induced by EPO and SCF. The increased numbers and survival of erythroid progenitors from fps(MF) mice, and their differential responsiveness to SCF and EPO, implicates Fps/Fes in the commitment of multilineage progenitors to the erythroid lineage. The anemic phenotype in fps(MF) mice suggests that downregulation of Fps/Fes activity might be required for terminal erythroid differentiation.
authors.affiliation: Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
authors.forename: Waheed
authors.initials: W
authors.lastname: Sangrar
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.forename: Barbara
authors.initials: B
authors.lastname: Bates
authors.forename: Ralph
authors.initials: R
authors.lastname: Zirngibl
authors.forename: Peter A
authors.initials: PA
authors.lastname: Greer
mesh_terms: D000740:Anemia / Q000209:etiology; D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival; D004789:Enzyme Activation / Q000502:physiology; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000201:enzymology*; D004921:Erythropoietin / Q000378:metabolism; D015681:Fusion Proteins, gag-onc / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D017467:Receptors, Erythropoietin / Q000378:metabolism; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology
chemical_list: D015681:Fusion Proteins, gag-onc; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin; D019089:Stem Cell Factor; C052602:proto-oncogene protein c-fes-fps; D004921:Erythropoietin; D011505:Protein-Tyrosine Kinases; C068415:v-fps oncogene protein, Fujinami sarcoma virus