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

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.

journal_name

Mol Cell Biol

authors

Funakoshi-Tago M,Pelletier S,Moritake H,Parganas E,Ihle JN

doi

10.1128/MCB.01447-07

subject

Has Abstract

pub_date

2008-03-01 00:00:00

pages

1792-801

issue

5

eissn

0270-7306

issn

1098-5549

pii

MCB.01447-07

journal_volume

28

pub_type

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