Two domains of the erythropoietin receptor are sufficient for Jak2 binding/activation and function

Stéphane Pelletier, Sébastien Gingras, Megumi Tago, Sherié Howell, James N. Ihle

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Biochemical and genetic studies have shown that Jakl is an essential component of EpoR signal transduction which is required for normal erythropoiesis. However, whether Jakl 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.

Original languageEnglish
Pages (from-to)8527-8538
Number of pages12
JournalMolecular and Cellular Biology
Volume26
Issue number22
DOIs
Publication statusPublished - 2006 Nov
Externally publishedYes

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Erythropoietin Receptors
Signal Transduction
Cytokine Receptors
Erythropoiesis
Cell Surface Receptors
Glycine
Molecular Biology
Cell Membrane
Membranes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Two domains of the erythropoietin receptor are sufficient for Jak2 binding/activation and function. / Pelletier, Stéphane; Gingras, Sébastien; Tago, Megumi; Howell, Sherié; Ihle, James N.

In: Molecular and Cellular Biology, Vol. 26, No. 22, 11.2006, p. 8527-8538.

Research output: Contribution to journalArticle

Pelletier, Stéphane ; Gingras, Sébastien ; Tago, Megumi ; Howell, Sherié ; Ihle, James N. / Two domains of the erythropoietin receptor are sufficient for Jak2 binding/activation and function. In: Molecular and Cellular Biology. 2006 ; Vol. 26, No. 22. pp. 8527-8538.
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