The Journal of Experimental Medicine
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Published online 8 March 2004 doi:10.1084/jem.20031109
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 6, 785-795
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Btk Is Required for an Efficient Response to Erythropoietin and for SCF-controlled Protection against TRAIL in Erythroid Progenitors

Uwe Schmidt1, Emile van den Akker2, Martine Parren-van Amelsvoort2, Gabi Litos1, Marella de Bruijn3, Laura Gutiérrez3, Rudi W. Hendriks4, Wilfried Ellmeier5, Bob Löwenberg2, Hartmut Beug1, and Marieke von Lindern2

1 Institute of Molecular Pathology, A-1030 Vienna, Austria
2 Department of Hematology, 3 Department of Cell Biology and Genetics, and 4 Department of Immunology, Erasmus Medical Center, 3015 DR Rotterdam, Netherlands
5 Institute of Immunology, University of Vienna, A-1030 Vienna, Austria

Address correspondence to Marieke von Lindern, Dept. of Hematology, Erasmus Medical Center, P.O. Box 1738, 3015 DR Rotterdam, Netherlands. Phone: 31-10-408-7961; Fax: 31-10-408-9470; email: m.vonlindern{at}erasmusmc.nl; or Hartmut Beug, Institute of Molecular Pathology, Dr. Bohrgasse 7, A-1030 Vienna, Austria. Phone: 43-1-79730-883; Fax: 43-1-79871-53; email: beug{at}nt.imp.univie.ac.at

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 PLC{gamma}1 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.

Key Words: Jak2 • Stat5 • hematopoiesis • signal transduction

U. Schmidt, E. van den Akker, H. Beug, and M. von Lindern contributed equally to this paper.

The online version of this article includes supplemental material.

The present address of M. de Bruijn is Medical Research Council Molecular Haematology Unit, Oxford OX3 9DS, UK.

The present address of U. Schmidt is the Institute of Immunology, University of Vienna, A-1235 Vienna, Austria.

Abbreviations used in this paper: Btk, Bruton's tyrosine kinase; Dex, dexamethasone; Epo, erythropoietin; MDS, myelodysplastic syndrome; PKC, protein kinase C; RE, reexpressing; SCF, stem cell factor; TCL, total cell lysate; TRAIL, TNF-related apoptosis-inducing ligand; TRAILR1, TRAIL receptor 1.


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