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J. Biol. Chem., Vol. 283, Issue 9, 5258-5266, February 29, 2008

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Dimerization by a Cytokine Receptor Is Necessary for Constitutive Activation of JAK2V617F^*

Xiaohui Lu, Lily Jun-Shen Huang, and Harvey F. Lodish^¶1

From the Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, the Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and the ^¶Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

The majority of the BCR-ABL-negative myeloproliferative disorders express the mutant JAK2, JAK2V617F. Previously we showed that constitutive activation of this oncogenic JAK2 mutant in Ba/F3 or 32D cells requires coexpression of a cognate homodimeric cytokine receptor, such as the EpoR. However, overexpression of JAK2V617F in Ba/F3 cells renders them cytokine-independent for growth in the absence of an exogenous cytokine receptor. Here, we demonstrated that JAK2V617F domains required for receptor association are essential for cytokine-independent growth by overexpressed JAK2V617F, suggesting JAK2V617F is binding to an unknown endogenous cytokine receptor(s) for its activation. We further showed that disruption of EpoR dimerization by coexpressing a truncated EpoR disrupted JAK2V617F-mediated transformation, indicating that EpoR dimerization plays an essential role in the activation of JAK2V617F. Interestingly, coexpression of JAK2V617F with EpoR mutants that retain JAK2 binding but are defective in mediating Epo-dependent JAK2 activation due to mutations in a conserved juxtamembrane motif does lead to cytokine-independent activation of JAK2V617F. Overall, these findings confirm that JAK2V617F requires binding to a dimerized cytokine receptor for its activation, and that the key EpoR juxtamembrane regulatory motif essential for Epo-dependent JAK2 activation is not essential for the activation of JAK2V617F. The structure of the activated JAK2V617F is thus likely to be different from that of the activated wild-type JAK2, raising the possibility of developing a specifically targeted therapy for myeloproliferative disorders.

Received for publication, August 24, 2007 , and in revised form, December 18, 2007.

^* This work was supported in part by National Institutes of Health Grant P01 HL 32262, and a research grant from Amgen, Inc. (to H. F. L.), and by National Institutes of Health Grant K01 CA95150 and Welch Foundation Grant I-1602 (to L. J. H.). 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: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142. Tel.: 617-258-5216; Fax: 617-258-6768; E-mail: lodish{at}wi.mit.edu.

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