JAK2V617F-Mediated Phosphorylation of PRMT5 Downregulates Its Methyltransferase Activity and Promotes Myeloproliferation

Fan Liu, Xinyang Zhao, Fabiana Perna, Lan Wang, Priya Koppikar, Omar Abdel-Wahab, Michael W. Harr, Ross L. Levine, Hao Xu, Ayalew Tefferi, Anthony Deblasio, Megan Hatlen, Silvia Menendez, Stephen D Nimer

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)283-294
Number of pages12
JournalCancer Cell
Volume19
Issue number2
DOIs
StatePublished - Feb 15 2011
Externally publishedYes

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Methyltransferases
Down-Regulation
Phosphorylation
Histones
Protein-Tyrosine Kinases
Small Interfering RNA
Chromatin
Carrier Proteins
Phosphotransferases
Phenotype
Neoplasms
human PRMT2 protein

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

JAK2V617F-Mediated Phosphorylation of PRMT5 Downregulates Its Methyltransferase Activity and Promotes Myeloproliferation. / Liu, Fan; Zhao, Xinyang; Perna, Fabiana; Wang, Lan; Koppikar, Priya; Abdel-Wahab, Omar; Harr, Michael W.; Levine, Ross L.; Xu, Hao; Tefferi, Ayalew; Deblasio, Anthony; Hatlen, Megan; Menendez, Silvia; Nimer, Stephen D.

In: Cancer Cell, Vol. 19, No. 2, 15.02.2011, p. 283-294.

Research output: Contribution to journalArticle

Liu, F, Zhao, X, Perna, F, Wang, L, Koppikar, P, Abdel-Wahab, O, Harr, MW, Levine, RL, Xu, H, Tefferi, A, Deblasio, A, Hatlen, M, Menendez, S & Nimer, SD 2011, 'JAK2V617F-Mediated Phosphorylation of PRMT5 Downregulates Its Methyltransferase Activity and Promotes Myeloproliferation', Cancer Cell, vol. 19, no. 2, pp. 283-294. https://doi.org/10.1016/j.ccr.2010.12.020
Liu, Fan ; Zhao, Xinyang ; Perna, Fabiana ; Wang, Lan ; Koppikar, Priya ; Abdel-Wahab, Omar ; Harr, Michael W. ; Levine, Ross L. ; Xu, Hao ; Tefferi, Ayalew ; Deblasio, Anthony ; Hatlen, Megan ; Menendez, Silvia ; Nimer, Stephen D. / JAK2V617F-Mediated Phosphorylation of PRMT5 Downregulates Its Methyltransferase Activity and Promotes Myeloproliferation. In: Cancer Cell. 2011 ; Vol. 19, No. 2. pp. 283-294.
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