The Pseudokinase Domain of JAK2 Is a Dual-Specificity Protein Kinase That Negatively Regulates Cytokine Signaling

摘要: Human JAK2 tyrosine kinase mediates signaling through numerous cytokine receptors. The JH2 domain functions as a negative regulator and is presumed to be catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of remains unknown. Mutations in lead increased activity, contributing myeloproliferative neoplasms (MPNs). Here we show that dual-specificity protein phosphorylates two regulatory sites JAK2: Ser523 Tyr570. Inactivation catalytic activity basal downstream signaling. Notably, different MPN mutations abrogated cells, (V617F) patient cells phosphorylation Tyr570 was reduced, suggesting loss contributes pathogenesis MPNs. These results identify previously unrecognized mechanism control JAK2.