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JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation.

Cancer cell | Feb 15, 2011

The JAK2V617F constitutively activated tyrosine kinase is found in most patients with myeloproliferative neoplasms. While examining the interaction between JAK2 and PRMT5, an arginine methyltransferase originally identified as JAK-binding protein 1, we found that JAK2V617F (and JAK2K539L) bound PRMT5 more strongly than did wild-type JAK2. These oncogenic kinases also acquired the ability to phosphorylate PRMT5, greatly impairing its ability to methylate its histone substrates, and representing a specific gain-of-function that allows them to regulate chromatin modifications. We readily detected PRMT5 phosphorylation in JAK2V617F-positive patient samples, and when we knocked down PRMT5 in human CD34+ cells using shRNA, we observed increased colony formation and erythroid differentiation. These results indicate that phosphorylation of PRMT5 contributes to the mutant JAK2-induced myeloproliferative phenotype.

Pubmed ID: 21316606 RIS Download

Mesh terms: Cell Line | Down-Regulation | Humans | Janus Kinase 2 | Mutation | Myeloproliferative Disorders | Phosphorylation | Protein Methyltransferases | Protein-Arginine N-Methyltransferases | Substrate Specificity

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA151949
  • Agency: NCI NIH HHS, Id: R01-CA151949

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