Activated Fps/Fes tyrosine kinase regulates erythroid differentiation and survival

• Published in: Experimental hematology 2004-10, Vol.32 (10), p.935-945
• Main Authors: Sangrar, Waheed, Gao, Yan, Bates, Barbara, Zirngibl, Ralph, Greer, Peter A.
• Format: Article
• Language: English
• Subjects: Anemia - etiology; Animals; Cell Differentiation; Cell Survival; Enzyme Activation - physiology; Erythroid Precursor Cells - cytology; Erythroid Precursor Cells - enzymology; Erythropoietin - metabolism; Fusion Proteins, gag-onc - metabolism; Fusion Proteins, gag-onc - physiology; Mice; Mice, Transgenic; Phosphorylation - drug effects; Protein-Tyrosine Kinases - metabolism; Protein-Tyrosine Kinases - physiology; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins - physiology; Receptors, Erythropoietin - metabolism; Signal Transduction; Stem Cell Factor - pharmacology
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2004.07.004

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. 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. 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. 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.