MYPT1/PP1‐Mediated EZH2 Dephosphorylation at S21 Promotes Epithelial–Mesenchymal Transition in Fibrosis through Control of Multiple Families of Genes

Abstract

The methyltransferase EZH2 plays an important role in regulating chromatin conformation and gene transcription. Phosphorylation of EZH2 at S21 by AKT kinase suppresses its function. However, protein phosphatases responsible for the dephosphorylation of EZH2-S21 remain elusive. Here, it is demonstrated that EZH2 is highly expressed in the ocular lens, and AKT-EZH2 axis is important in TGF𝜷-induced epithelial-mesenchymal transition (EMT). More importantly, it is identified that MYPT1/PP1 dephosphorylates EZH2-S21 and thus modulates its functions. MYPT1 knockout accelerates EMT, but expression of the EZH2-S21A mutant suppresses EMT through control of multiple families of genes. Furthermore, the phosphorylation status and gene expression modulation of EZH2 are implicated in control of anterior subcapsular cataracts (ASC) in human and mouse eyes. Together, the results identify the specific phosphatase for EZH2-S21 and reveal EZH2 dephosphorylation control of several families of genes implicated in lens EMT and ASC pathogenesis. These results provide important novel information in EZH2 function and regulation.

The lysophosphatidic acid-regulated signal transduction network in ovarian cancer cells and its role in actomyosin dynamics, cell migration and entosis

“…6 A and B), a role for a PKCδ/ERK -| MYPT1 signaling in pathways other than MLC2 regulation is likely. This hypothesis is compatible with the identification of MYPT1 targets other than MLC2 108 - 111 and is discussed in more detail below. S507 phosphorylation was also inhibited by Y27632, albeit with a considerably lower effect compared to p-MLC2 (Fig.…”

“…This hypothesis is supported by the observation that excessive tension induced by high myosin II activity reduces membrane protrusion and migration velocity 115 . However, functions of MYPT1 other than MLC2 regulation may also be involved 108 - 111 . Of particular interest in this context may be the reported regulation of the Hippo pathway by MYPT1 116 , as the Hippo-regulated transcription factor TAZ (WWTR1) is subject to LPA-regulated dephosphorylation ( Table S9 ), and Hippo signaling has been implicated in cytoskeletal organization 117 , cancer cell migration 116 as well as OC progression 118 .…”

“…The indicated enhancement of PP1 - MLC2 interaction is based on published observations 62 . MYPT1 targets other than MLC2, including EZH2 111 , PLK1 108 and regulators of the Hippo pathway 109 have been described.…”

Long Non-Coding RNA H19 Prevents Lens Fibrosis through Maintaining Lens Epithelial Cell Phenotypes

“…Many studies have been conducted to explore the potential therapeutic options for preventing or reversing lens fibrosis using diverse experimental models. To better validate their roles in lens transparency maintenance, in recent years, apart from in vitro studies using lens epithelial cell lines, semi-in vivo epithelial explants, the whole lens culturing, and in vivo animal models have been more widely used, including injury-induced ASC models, mock lens cataract surgery (Extracapsular Lens Extraction, ECLE) for PCO models, and transgenic/genetic knockout mice [ 19 , 52 , 53 , 54 , 55 , 56 , 57 ]. It is generally accepted that during TGF-β2-induced EMT, loss of LEC integrity is accompanied by the abnormal secretion of ECM and aberrant cell migration, resulting in fibrotic plaques and lens opacification.…”

“…Accumulative studies have pointed out that TGF-β2-induced EMT is a crucial feature manifested in embryonic development and various pathological phenomena, particularly wound healing, fibrotic diseases, and some invasive cancers [ 15 , 16 , 17 ]. EMT triggers lens fibrosis and can be targeted at multiple levels [ 18 , 19 , 20 ]. Long non-coding RNAs (LncRNAs) are a group of RNAs whose length exceeds 200 nucleotides but cannot be translated into functional proteins [ 21 ].…”