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Molecular and Cellular Biology, November 2006, p. 8527-8538, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.01035-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Two Domains of the Erythropoietin Receptor Are Sufficient for Jak2 Binding/Activation and Function{triangledown}

Stéphane Pelletier, Sébastien Gingras, Megumi Funakoshi-Tago, Sherié Howell, and James N. Ihle*

Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Received 8 June 2006/ Returned for modification 14 July 2006/ Accepted 1 September 2006

Biochemical and genetic studies have shown that Jak2 is an essential component of EpoR signal transduction which is required for normal erythropoiesis. However, whether Jak2 is the sole direct mediator of EpoR signal transduction remains controversial. To address this issue, we have used an extensive and systematic mutational analysis across the EpoR cytoplasmic tail and transmembrane domain with the goal of determining whether mutants that negatively affected EpoR biological activity but retained Jak2 activation could be identified. Analysis of over 40 mutant receptors established that two large domains in the membrane-proximal region, which include the previously defined Box1 and Box2 domains as well as a highly conserved glycine among cytokine receptors, are required for Jak2 binding and activation and to sustain biological activity of the receptor. Importantly, none of the mutants that lost the ability to activate Jak2 retained the ability to bind Jak2, thus questioning the validity of models of receptor reorientation for Jak2 activation. Also, no correlation was made between cell surface expression of the receptor and its ability to bind Jak2, thus questioning the role of Jak2 in trafficking the receptor to the plasma membrane. Collectively, the results suggest that Jak2 is the sole direct signaling molecule downstream of EpoR required for biological activity.

* Corresponding author. Mailing address: Department of Biochemistry, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105. Phone: (901) 495-2474. Fax: (901) 525-8025. E-mail: jihle.mcb{at}stjude.org.

{triangledown} Published ahead of print on 18 September 2006.

Molecular and Cellular Biology, November 2006, p. 8527-8538, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.01035-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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