title: JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation.
abstract: 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.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.forename: Xinyang
authors.initials: X
authors.lastname: Zhao
authors.forename: Fabiana
authors.initials: F
authors.lastname: Perna
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.forename: Priya
authors.initials: P
authors.lastname: Koppikar
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Michael W
authors.initials: MW
authors.lastname: Harr
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
authors.forename: Anthony
authors.initials: A
authors.lastname: Deblasio
authors.forename: Megan
authors.initials: M
authors.lastname: Hatlen
authors.forename: Silvia
authors.initials: S
authors.lastname: Menendez
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
mesh_terms: D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009196:Myeloproliferative Disorders; D010766:Phosphorylation; D011496:Protein Methyltransferases / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases; D013379:Substrate Specificity
chemical_list: D011496:Protein Methyltransferases; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D053614:Janus Kinase 2