Btk is required for an efficient response to erythropoietin and for SCF-controlled protection against TRAIL in erythroid progenitors.
Regulation of survival, expansion, and differentiation of erythroid progenitors requires the well-controlled activity of signaling pathways induced by erythropoietin (Epo) and stem cell factor (SCF). In addition to qualitative regulation of signaling pathways, quantitative control may be essential to control appropriate cell numbers in peripheral blood. We demonstrate that Bruton's tyrosine kinase (Btk) is able to associate with the Epo receptor (EpoR) and Jak2, and is a substrate of Jak2. Deficiency of Btk results in reduced and delayed phosphorylation of the EpoR, Jak2, and downstream signaling molecules such as Stat5 and PLCgamma1 as well as in decreased responsiveness to Epo. As a result, expansion of erythroid progenitors lacking Btk is impaired at limiting concentrations of Epo and SCF. In addition, we show that SCF induces Btk to interact with TNF-related apoptosis-inducing ligand (TRAIL)-receptor 1 and that lack of Btk results in increased sensitivity to TRAIL-induced apoptosis. Together, our results indicate that Btk is a novel, quantitative regulator of Epo/SCF-dependent expansion and survival in erythropoiesis.
Institute of Molecular Pathology, Vienna, Austria.
Uwe
U
Schmidt
Emile
E
van den Akker
Martine
M
Parren-van Amelsvoort
Gabi
G
Litos
Marella
M
de Bruijn
Laura
L
Gutiérrez
Rudi W
RW
Hendriks
Wilfried
W
Ellmeier
Bob
B
Löwenberg
Hartmut
H
Beug
Marieke
M
von Lindern
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000911:Antibodies, Monoclonal; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D015672:Erythroid Precursor Cells / Q000502:physiology*; D004921:Erythropoietin / Q000378:metabolism* / Q000502:physiology; D005434:Flow Cytometry; D006454:Hemoglobins / Q000378:metabolism; D053614:Janus Kinase 2; D010957:Plasmids / Q000235:genetics; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019089:Stem Cell Factor / Q000378:metabolism* / Q000502:physiology; D014162:Transfection
D000911:Antibodies, Monoclonal; D006454:Hemoglobins; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D019089:Stem Cell Factor; C105190:TNFRSF10A protein, human; D004921:Erythropoietin; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2