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J. Biol. Chem., Vol. 281, Issue 12, 7697-7707, March 24, 2006

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Profiling of Early Gene Expression Induced by Erythropoietin Receptor Structural Variants^*

From the Institute of Medical Biochemistry and Molecular Biology, Medical Faculty, University of Rostock, 18057 Rostock, Germany

The development of erythroid progenitor cells is triggered via the expression of the erythropoietin receptor (EPOR) and its activation by erythropoietin. The function of the resulting receptor complex depends critically on the presence of activated JAK2, and the complex contains a large number of signaling molecules recruited to eight phosphorylated tyrosine residues. Studies using mutant receptor forms have demonstrated that truncated receptors lacking all tyrosines are able to support red blood cell development with low efficiency, whereas add-back mutants containing either Tyr³⁴³ or Tyr⁴⁷⁹ reconstitute EPOR signaling and erythropoiesis in vivo. To study the contribution of tyrosines to receptor function, we analyzed the activation of essential signaling pathways and early gene induction promoted by different receptor structural variants using human epidermal growth factor receptor/murine EPOR hybrids. In our experiments, receptors lacking all tyrosine residues or the JAK2-binding site did not induce mitogenic and anti-apoptotic signaling, whereas add-back mutant receptors containing single tyrosine residues (Try³⁴³ and Tyr⁴⁷⁹) supported the activation of these functions efficiently. Profiling of early gene expression using cDNA array hybridization revealed that (i) the high redundancy in the activation of signaling pathways is continued at the level of transcription; (ii) the expression of many genes targeted by the wild-type receptor is not supported by add-back mutants; and (iii) a small set of genes are exclusively induced by add-back receptors. We report the identification of several early genes that have not been implicated in the EPOR-dependent response so far.

Received for publication, August 2, 2005 , and in revised form, December 23, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant Bi599/2-1 (to T. Bittorf). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Inst. of Medical Biochemistry and Molecular Biology, Medical Faculty, University of Rostock, Schillingallee 70, 18057 Rostock, Germany. Tel.: 49-381-494-5756; Fax: 49-381-494-5752; E-mail: thomas.bittorf{at}med.uni-rostock.de.

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