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

Fan Liu1, Xinyang Zhao, Fabiana Perna

  • 1Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Cancer Cell
|February 15, 2011
PubMed

Insights

Mutant JAK2 kinases bind and phosphorylate PRMT5, impairing its function in myeloproliferative neoplasms. This phosphorylation contributes to the disease phenotype by affecting chromatin modifications and cell differentiation.

Area of Science:

  • Molecular Biology
  • Oncology
  • Epigenetics

Background:

  • The JAK2V617F mutation is prevalent in myeloproliferative neoplasms (MPNs).
  • PRMT5, an arginine methyltransferase, interacts with JAK2.
  • Understanding the JAK2-PRMT5 interaction is crucial for MPN pathogenesis.

Purpose of the Study:

  • To investigate the interaction between JAK2V617F and PRMT5.
  • To determine the functional consequences of this interaction on PRMT5 activity and chromatin modification.
  • To explore the role of PRMT5 phosphorylation in MPN development.

Main Methods:

  • Studied the binding affinity between wild-type JAK2, JAK2V617F, JAK2K539L, and PRMT5.
  • Assessed PRMT5 phosphorylation by oncogenic JAK2 mutants.
  • Measured PRMT5's histone methylation activity.
  • Analyzed PRMT5 phosphorylation in patient samples.
  • Utilized shRNA to knock down PRMT5 in human CD34+ cells.

Main Results:

  • JAK2V617F and JAK2K539L exhibit stronger binding to PRMT5 compared to wild-type JAK2.
  • Oncogenic JAK2 mutants phosphorylate PRMT5, significantly reducing its histone methyltransferase activity.
  • PRMT5 phosphorylation by mutant JAK2 impairs its ability to regulate chromatin modifications.
  • PRMT5 phosphorylation was detected in JAK2V617F-positive patient samples.
  • PRMT5 knockdown in CD34+ cells led to increased colony formation and erythroid differentiation.

Conclusions:

  • Phosphorylation of PRMT5 by mutant JAK2 is a gain-of-function mechanism.
  • This phosphorylation contributes to the myeloproliferative phenotype observed in MPNs.
  • Targeting PRMT5 phosphorylation may offer a therapeutic strategy for MPNs.

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