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J Biol Chem. 2018 Aug 24;293(34):13059-13072. doi: 10.1074/jbc.RA118.002027. Epub 2018 Jun 15.

Arginine methylation of SMAD7 by PRMT1 in TGF-β-induced epithelial-mesenchymal transition and epithelial stem-cell generation.

Author information

1
From the Department of Cell and Tissue Biology and Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research.
2
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, and.
3
Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry and.
4
Central Laboratory, Renmin Hospital, Wuhan University, Wuhan, Hubei 430060, China.
5
Departments of Pharmaceutical Chemistry and.
6
From the Department of Cell and Tissue Biology and Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, xujian@usc.edu.
7
Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
8
From the Department of Cell and Tissue Biology and Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, rik.derynck@ucsf.edu.
9
Anatomy, and.
10
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143.

Abstract

The epithelial-to-mesenchymal transdifferentiation (EMT) is crucial for tissue differentiation in development and drives essential steps in cancer and fibrosis. EMT is accompanied by reprogramming of gene expression and has been associated with the epithelial stem-cell state in normal and carcinoma cells. The cytokine transforming growth factor β (TGF-β) drives this program in cooperation with other signaling pathways and through TGF-β-activated SMAD3 as the major effector. TGF-β-induced SMAD3 activation is inhibited by SMAD7 and to a lesser extent by SMAD6, and SMAD6 and SMAD7 both inhibit SMAD1 and SMAD5 activation in response to the TGF-β-related bone morphogenetic proteins (BMPs). We previously reported that, in response to BMP, protein arginine methyltransferase 1 (PRMT1) methylates SMAD6 at the BMP receptor complex, thereby promoting its dissociation from the receptors and enabling BMP-induced SMAD1 and SMAD5 activation. We now provide evidence that PRMT1 also facilitates TGF-β signaling by methylating SMAD7, which complements SMAD6 methylation. We found that PRMT1 is required for TGF-β-induced SMAD3 activation, through a mechanism similar to that of BMP-induced SMAD6 methylation, and thus promotes the TGF-β-induced EMT and epithelial stem-cell generation. This critical mechanism positions PRMT1 as an essential mediator of TGF-β signaling that controls the EMT and epithelial cell stemness through SMAD7 methylation.

KEYWORDS:

SMAD transcription factor; arginine methyltransferase; cancer stem cells; cell surface receptor; epithelial cell; epithelial stem cell; epithelial-mesenchymal transition; post-translational modification (PTM); stemness

PMID:
29907569
PMCID:
PMC6109915
[Available on 2019-08-24]
DOI:
10.1074/jbc.RA118.002027

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