Control of erythropoiesis by erythropoietin and stem cell factor: a novel role for Bruton's tyrosine kinase.
Erythropoietin (Epo) and stem cell factor (SCF) are essential factors in the control of survival, expansion and differentiation of erythroid progenitors. Upon activation, their receptors, the EpoR and c-Kit, initiate multiple signalling pathways that control many cellular processes. To control erythropoiesis, the strength, duration and specificity of signalling must be tightly controlled. Negative feed-back regulation is extensively studied, but positive feed-forward control is relatively little studied. The cytoplasmic tyrosine kinase Bruton's tyrosine kinase (Btk) was found to be phosphorylated by Jak2 in response to Epo and appeared to be required for fast and efficient phosphorylation of Epo-induced targets including the EpoR itself and downstream targets such as PLCgamma and Stat5. Erythroid progenitors deficient in Btk fail to undergo renewal divisions and differentiate instead at low, physiologic concentrations of Epo and SCF. In addition, Btk is phosphorylated by SCF, which causes association of Btk with TRAIL-receptor1. In absence of Btk, erythroid progenitors are hypersensitive to TRAIL. Thus, Btk modulates signalling in erythroid progenitors to enhance expansion of erythroid progenitors. The complexity of signalling by the EpoR/c-Kit signalosome and its control by Btk is discussed with respect to normal and aberrant erythropoiesis.
von Lindern
Marieke
M
Department of Hematology, Erasmus MC, Rotterdam, The Netherlands. m.vonlindern@erasmusmc.nl
Schmidt
Uwe
U
Beug
Hartmut
H
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D015672:Erythroid Precursor Cells / Q000378:metabolism*; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019089:Stem Cell Factor / Q000378:metabolism*
D017467:Receptors, Erythropoietin; D019089:Stem Cell Factor; D004921:Erythropoietin; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human