Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 28, Issue 5, Pages 1792-1801Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01447-07
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Funding
- NCI NIH HHS [CA21765, P30 CA021765] Funding Source: Medline
- NHLBI NIH HHS [P01 HL53740] Funding Source: Medline
- NIDDK NIH HHS [R01 DK42932, R01 DK042932] Funding Source: Medline
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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.
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