Related Experiment Video
Updated: Nov 29, 2025

Quantitative Methods to Study Protein Arginine Methyltransferase 1-9 Activity in Cells
Published on: August 7, 2021
Stabilization of ERK-Phosphorylated METTL3 by USP5 Increases m6A Methylation
Hui-Lung Sun1, Allen C Zhu2, Yawei Gao3
1Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
Abstract:
N6-methyladenosine (m6A) is the most abundant mRNA modification and is installed by the METTL3-METTL14-WTAP methyltransferase complex. Although the importance of m6A methylation in mRNA metabolism has been well documented recently, regulation of the m6A machinery remains obscure. Through a genome-wide CRISPR screen, we identify the ERK pathway and USP5 as positive regulators of the m6A deposition. We find that ERK phosphorylates METTL3 at S43/S50/S525 and WTAP at S306/S341, followed by deubiquitination by USP5, resulting in stabilization of the m6A methyltransferase complex. Lack of METTL3/WTAP phosphorylation reduces decay of m6A-labeled pluripotent factor transcripts and traps mouse embryonic stem cells in the pluripotent state. The same phosphorylation can also be found in ERK-activated human cancer cells and contribute to tumorigenesis. Our study reveals an unrecognized function of ERK in regulating m6A methylation.
Related Concept Videos
Covalently Linked Protein Regulators
These groups modify specific amino acids in a protein....
RNA Stability
The Unfolded Protein Response
mRNA Stability and Gene Expression
Cis-acting Elements involved in mRNA stability
PI3K/mTOR/AKT Signaling Pathway
Microtubule Instability

