Jak2 FERM domain interaction with the erythropoietin receptor regulates Jak2 kinase activity

Megumi Tago, Stéphane Pelletier, Hiroshi Moritake, Evan Parganas, James N. Ihle

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Janus kinases are essential for signal transduction by a variety of cytokine receptors and when inappropriately activated can cause hematopoietic disorders and oncogenesis. Consequently, it can be predicted that the interaction of the kinases with receptors and the events required for activation are highly controlled. In a screen to identify phosphorylation events regulating Jak2 activity in EpoR signaling, we identified a mutant (Jak2-Y613E) which has the property of being constitutively activated, as well as an inactivating mutation (Y766E). Although no evidence was obtained to indicate that either site is phosphorylated in signaling, the consequences of the Y613E mutation are similar to those observed with recently described activating mutations in Jak2 (Jak2-V617F and Jak2-L611S). However, unlike the V617F or L611S mutant, the Y613E mutant requires the presence of the receptor but not Epo stimulation for activation and downstream signaling. The properties of the Jak2-Y613E mutant suggest that under normal conditions, Jak2 that is not associated with a receptor is locked into an inactive state and receptor binding through the FERM domain relieves steric constraints, allowing the potential to be activated with receptor engagement.

Original languageEnglish
Pages (from-to)1792-1801
Number of pages10
JournalMolecular and Cellular Biology
Volume28
Issue number5
DOIs
Publication statusPublished - 2008 Mar
Externally publishedYes

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Erythropoietin Receptors
Phosphotransferases
Mutation
Janus Kinases
Cytokine Receptors
Signal Transduction
Carcinogenesis
Phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Genetics

Cite this

Jak2 FERM domain interaction with the erythropoietin receptor regulates Jak2 kinase activity. / Tago, Megumi; Pelletier, Stéphane; Moritake, Hiroshi; Parganas, Evan; Ihle, James N.

In: Molecular and Cellular Biology, Vol. 28, No. 5, 03.2008, p. 1792-1801.

Research output: Contribution to journalArticle

Tago, Megumi ; Pelletier, Stéphane ; Moritake, Hiroshi ; Parganas, Evan ; Ihle, James N. / Jak2 FERM domain interaction with the erythropoietin receptor regulates Jak2 kinase activity. In: Molecular and Cellular Biology. 2008 ; Vol. 28, No. 5. pp. 1792-1801.
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