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

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.

Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation

“…Protein arginine methyltransferase 1 (PRMT1) is necessary for "TGF-b-induced SMAD3 activation through a mechanism similar to that of TGF-b-related bone morphogenetic protein (BMP) induced SMAD6 methylation, and thus promotes the TGF-b-induced EMT and epithelial stem-cell generation" [247]. SMAD7 inhibits the TGF-b-induced SMAD3 activation but PRMT1 induced SMAD 7 methlyation enables and facilitates TGF-b signaling.…”

Differentiation and Establishment of Dental Epithelial-Like Stem Cells Derived from Human ESCs and iPSCs

“…It is well-known that protein arginine methyltransferase 1 (PRMT1) enables TGF-signaling to regulate EMT and the stemness of epithelial cells through SMAD6 methylation at the bone morphogenic protein (BMP) receptor complex, and thus promotes the TGF-induced EMT and epithelial stem-cell generation [49]. Moreover, by using media containing bFGF, VEGF, EGF, and R3-IGF-1, hESCs could differentiate into an epithelial sheet and obtain EMT characteristics [50].…”

Current perspectives on inhibitory SMAD7 in health and disease

“…This methylation of SMAD7 significantly increased the interaction with E3 ubiquitin ligase Arkadia (also termed RNF111), facilitating SMAD7 ubiquitination and proteasomal degradation (Elkouris et al 2016). SMAD7 is also a substrate for PRMT1, another methyltransferase (Inamitsu et al 2006;Katsuno et al 2018). Arg-57 and Arg-67 methylation of SMAD7 by PRMT1 led to lowered TbRI-binding efficiency and increased degradation of SMAD7.…”