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The MKK-Dependent Phosphorylation of p38α Is Augmented by Arginine Methylation on Arg49/Arg149 during Erythroid

Mei-Yin Liu1, Wei-Kai Hua1, Chi-Ju Chen2

  • 1Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan.

International Journal of Molecular Sciences
|May 21, 2020
PubMed

Insights

Protein arginine methylation by PRMT1 activates p38α signaling. This novel mechanism enhances interactions with upstream and downstream partners, promoting erythroid differentiation.

Area of Science:

  • Cellular signaling pathways
  • Epigenetics and post-translational modifications
  • Hematopoiesis and cell differentiation

Background:

  • p38 mitogen-activated protein kinases (MAPKs) are crucial regulators of cellular processes.
  • Canonical p38α activation occurs via phosphorylation cascades.
  • The role of post-translational modifications beyond phosphorylation in p38α regulation is less understood.

Purpose of the Study:

  • To investigate a novel activation mechanism for p38α.
  • To elucidate the role of protein arginine methylation in p38α function.
  • To explore the impact of methylation on p38α interactions and downstream effects in erythroid differentiation.

Main Methods:

  • Site-directed mutagenesis to create non-methylation mutants (R49/149K) of p38α.
  • Biochemical assays to assess protein-protein interactions between p38α, MKK3, and MAPKAPK2.
  • Analysis of p38α methylation levels by PRMT1.
  • Functional assays evaluating the effect of p38α mutations on erythroid differentiation.

Main Results:

  • Protein arginine methyltransferase 1 (PRMT1) methylates Arg49 and Arg149 of p38α.
  • Mutation of R49/149 to Lysine (R49/149K) abolished the promotive effect of p38α on erythroid differentiation.
  • PRMT1-mediated methylation enhances the interaction between p38α and its upstream kinase MKK3.
  • Methylation also impacts the interaction between p38α and its downstream effector MAPKAPK2.
  • MKK3-mediated phosphorylation of the R49/149K mutant p38α was significantly reduced.
  • Methylation of p38α by PRMT1 is independent of MKK3-mediated phosphorylation.

Conclusions:

  • A novel regulatory mechanism for p38α activation via protein arginine methylation on R49/R149 by PRMT1 has been identified.
  • This methylation process is critical for p38α function in promoting erythroid differentiation by modulating partner interactions.
  • The findings reveal new insights into the complex regulation of p38α signaling and suggest potential therapeutic targets.
Keywords:
MKK3arginine methylationerythroid differentiationp38 MAPKphosphorylation, PRMT1

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