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

Cancer cell | Feb 15, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21316606

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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