scholarly journals A dual role of YAP in driving TGFβ-mediated endothelial-to-mesenchymal transition

2021 ◽  
Vol 134 (15) ◽  
Author(s):  
Cecilia Savorani ◽  
Matteo Malinverno ◽  
Roberta Seccia ◽  
Claudio Maderna ◽  
Monica Giannotta ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Bmp Signaling ◽  
Early Gene ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition ◽  
Pathological Conditions ◽  
Candidate Target ◽  
Smad3 Phosphorylation ◽  
Endothelial To Mesenchymal Transition

ABSTRACT Endothelial-to-mesenchymal transition (EndMT) is the biological process through which endothelial cells transdifferentiate into mesenchymal cells. During embryo development, EndMT regulates endocardial cushion formation via TGFβ/BMP signaling. In adults, EndMT is mainly activated during pathological conditions. Hence, it is necessary to characterize molecular regulators cooperating with TGFβ signaling in driving EndMT, to identify potential novel therapeutic targets to treat these pathologies. Here, we studied YAP, a transcriptional co-regulator involved in several biological processes, including epithelial-to-mesenchymal transition (EMT). As EndMT is the endothelial-specific form of EMT, and YAP (herein referring to YAP1) and TGFβ signaling cross-talk in other contexts, we hypothesized that YAP contributes to EndMT by modulating TGFβ signaling. We demonstrate that YAP is required to trigger TGFβ-induced EndMT response, specifically contributing to SMAD3-driven EndMT early gene transcription. We provide novel evidence that YAP acts as SMAD3 transcriptional co-factor and prevents GSK3β-mediated SMAD3 phosphorylation, thus protecting SMAD3 from degradation. YAP is therefore emerging as a possible candidate target to inhibit pathological TGFβ-induced EndMT at early stages.

scholarly journals Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium

2019 ◽  
Vol 216 (8) ◽  
pp. 1874-1890 ◽  
Author(s):  
Nicolas Ricard ◽  
Rizaldy P. Scott ◽  
Carmen J. Booth ◽  
Heino Velazquez ◽  
Nicholas A. Cilfone ◽  
...  
Keyword(s):  
Rapid Onset ◽  
Cardiac Conduction ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition ◽  
Endothelin 1 ◽  
Endocrine Organs ◽  
Endothelial To Mesenchymal Transition

To define the role of ERK1/2 signaling in the quiescent endothelium, we induced endothelial Erk2 knockout in adult Erk1−/− mice. This resulted in a rapid onset of hypertension, a decrease in eNOS expression, and an increase in endothelin-1 plasma levels, with all mice dying within 5 wk. Immunostaining and endothelial fate mapping showed a robust increase in TGFβ signaling leading to widespread endothelial-to-mesenchymal transition (EndMT). Fibrosis affecting the cardiac conduction system was responsible for the universal lethality in these mice. Other findings included renal endotheliosis, loss of fenestrated endothelia in endocrine organs, and hemorrhages. An ensemble computational intelligence strategy, comprising deep learning and probabilistic programing of RNA-seq data, causally linked the loss of ERK1/2 in HUVECs in vitro to activation of TGFβ signaling, EndMT, suppression of eNOS, and induction of endothelin-1 expression. All in silico predictions were verified in vitro and in vivo. In summary, these data establish the key role played by ERK1/2 signaling in the maintenance of vascular normalcy.

scholarly journals Epicardial TGFβ and BMP Signaling in Cardiac Regeneration: What Lesson Can We Learn from the Developing Heart?

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 404
Author(s):  
Esther Dronkers ◽  
Manon M. M. Wauters ◽  
Marie José Goumans ◽  
Anke M. Smits
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Current Knowledge ◽  
Transforming Growth Factor Β ◽  
Heart Tissue ◽  
Vital Role ◽  
Bmp Signaling ◽  
Mesenchymal Transition ◽  
Starting Point

The epicardium, the outer layer of the heart, has been of interest in cardiac research due to its vital role in the developing and diseased heart. During development, epicardial cells are active and supply cells and paracrine cues to the myocardium. In the injured adult heart, the epicardium is re-activated and recapitulates embryonic behavior that is essential for a proper repair response. Two indispensable processes for epicardial contribution to heart tissue formation are epithelial to mesenchymal transition (EMT), and tissue invasion. One of the key groups of cytokines regulating both EMT and invasion is the transforming growth factor β (TGFβ) family, including TGFβ and Bone Morphogenetic Protein (BMP). Abundant research has been performed to understand the role of TGFβ family signaling in the developing epicardium. However, less is known about signaling in the adult epicardium. This review provides an overview of the current knowledge on the role of TGFβ in epicardial behavior both in the development and in the repair of the heart. We aim to describe the presence of involved ligands and receptors to establish if and when signaling can occur. Finally, we discuss potential targets to improve the epicardial contribution to cardiac repair as a starting point for future investigation.

scholarly journals Molecular Activation of the Kv11.1 Channel Reprograms EMT in Colon Cancer by Inhibiting TGFβ Signaling via Activation of Calcineurin

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6025
Author(s):  
Najmeh Eskandari ◽  
Vitalyi Senyuk ◽  
Jennifer Moore ◽  
Zane Kalik ◽  
Qiyue Luan ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Vital Role ◽  
Colon Cancer Cells ◽  
Strong Inhibition ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition ◽  
Stimulation Of

Control of ionic gradients is critical to maintain cellular homeostasis in both physiological and pathological conditions, but the role of ion channels in cancer cells has not been studied thoroughly. In this work we demonstrated that activity of the Kv11.1 potassium channel plays a vital role in controlling the migration of colon cancer cells by reversing the epithelial-to-mesenchymal transition (EMT) into the mesenchymal-to-epithelial transition (MET). We discovered that pharmacological stimulation of the Kv11.1 channel with the activator molecule NS1643 produces a strong inhibition of colon cancer cell motility. In agreement with the reversal of EMT, NS1643 treatment leads to a depletion of mesenchymal markers such as SNAIL1, SLUG, TWIST, ZEB, N-cadherin, and c-Myc, while the epithelial marker E-cadherin was strongly upregulated. Investigating the mechanism linking Kv11.1 activity to reversal of EMT into MET revealed that stimulation of Kv11.1 produced a strong and fast inhibition of the TGFβ signaling. Application of NS1643 resulted in de-phosphorylation of the TGFβ downstream effectors R-SMADs by activation of the serine/threonine phosphatase PP2B (calcineurin). Consistent with the role of TGFβ in controlling cancer stemness, NS1643 also produced a strong inhibition of NANOG, SOX2, and OCT4 while arresting the cell cycle in G0/G1. Our data demonstrate that activation of the Kv11.1 channel reprograms EMT into MET by inhibiting TGFβ signaling, which results in inhibition of motility in colon cancer cells.

Endothelial-to-Mesenchymal Transition: Role in Cardiac Fibrosis

2020 ◽  
Vol 26 (1) ◽  
pp. 3-11
Author(s):  
Weijia Cheng ◽  
Xiao Li ◽  
Dongling Liu ◽  
Chaochu Cui ◽  
Xianwei Wang
Keyword(s):  
Cardiovascular Diseases ◽  
Cardiac Fibrosis ◽  
Mesenchymal Cell ◽  
Therapeutic Interventions ◽  
Potential Implication ◽  
Mesenchymal Transition ◽  
Pathological Conditions ◽  
Complex Biological Process ◽  
Endothelial To Mesenchymal Transition

Endothelial-to-mesenchymal transition (EndMT) is a complex biological process by which endothelial cells lose their endothelial cell characteristics and acquire mesenchymal cell properties under certain physiological or pathological conditions. Recently, it has been found that EndMT plays an important role in the occurrence and development of fibrotic cardiovascular diseases. In this review, we first summarize the main induction pathways involved in EndMT process. In addition, we discuss the role of EndMT in fibrotic cardiovascular diseases and its potential implication in new therapeutic interventions.

scholarly journals WDR5 regulates epithelial-to-mesenchymal transition in breast cancer cellsviaTGFβ

2018 ◽  
Author(s):  
Punzi Simona ◽  
Balestrieri Chiara ◽  
D’Alesio Carolina ◽  
Bossi Daniela ◽  
Dellino Gaetano Ivan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Transcriptional Repression ◽  
Epithelial To Mesenchymal Transition ◽  
Active Role ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition ◽  
Luminal B ◽  
Tumor Plasticity

AbstractEven if the mortality rate in breast cancer (BC) has recently decreased, development of metastases and drug resistance are still challenges to successful systemic treatment. The epithelial-to-mesenchymal transition (EMT), as well as epigenetic dynamic modifications, plays a pivotal role in invasion, metastasis, and drug resistance. Here, we report that WDR5, the core subunit of histone H3 K4 methyltransferase complexes, is crucial in coordinating EMT and regulating epigenetic changes that drive metastasis. We show that silencing of WDR5 in BC up-regulates an epithelial signature in triple negative and luminal B like patients by transcriptional repression of mesenchymal genes and reduction of the metastatic properties of these cells. Moreover, we demonstrate that this regulation is mediated by inhibition of the TGFβ signaling both at the transcriptional and post-translational level, suggesting an active role of WDR5 in guiding tumor plasticity upon oncogenic insults, regardless of the pathological BC subtypes.We therefore suggest that WDR5 inhibition could be a successful pharmacologic approach to inhibit EMT and sensitize breast cancer cells to chemotherapy.

scholarly journals TGFβ mediated structural remodeling facilitates optic fissure fusion and the necessity of BMP antagonism in this process

2017 ◽  
Author(s):  
Max D. Knickmeyer ◽  
Juan L. Mateo ◽  
Priska Eckert ◽  
Eleni Roussa ◽  
Belal Rahhal ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Bmp Signaling ◽  
Model Systems ◽  
Tgfβ Signaling ◽  
Ecm Remodeling ◽  
Mesenchymal Transition ◽  
Morphogenetic Protein ◽  
Bmp Antagonists

AbstractThe optic fissure is a transient gap in the developing vertebrate eye, which must be closed as development proceeds. A persisting optic fissure, coloboma, is a major cause for blindness in children. Multiple factors are genetically linked to coloboma formation. However, especially the process of optic fissure fusion is still largely elusive on a cellular and molecular basis.We found a coloboma phenotype in mice with a targeted inactivation of the transforming growth factor 2 (TGFβ2). Here the optic fissure margins got in touch, however, failed to fuse. Transcriptomic analyses indicated TGFβ mediated ECM remodeling during optic fissure fusion. For functional analyses, we switched model systems and made use of zebrafish. We found TGFβ ligands expressed in the developing zebrafish eye, and the ligand binding receptor in the optic fissure. Using a new in vivo TGFβ signaling reporter, we also found active TGFβ signaling in the margins of the optic fissure. We addressed the function of Cadherin 6 (cdh6), one of the TGFβ regulated genes, by knock down experiments in zebrafish and found a prominent coloboma phenotype. Cdh6 was often found involved in processes of epithelial to mesenchymal transition (EMT), strengthening our hypothesis that an EMT-like process is also necessary for optic fissure fusion. Furthermore, we found Gremlin 2b (grem2b) and Follistatin a (fsta), homologs of TGFβ regulated bone morphogenetic protein (BMP) antagonists, expressed in the optic fissure margins, indicating the necessity of a localized inhibition of BMP signaling. Finally, we show that induced BMP expression is sufficient to inhibit optic fissure fusion. Together with our previous findings this indicates a dual role of BMP signaling during optic fissure closure.Summary statementTGFβ is crucial for optic fissure fusion, involving cdh6. TGFβ mediated optic fissure fusion is potentially hampered by BMP signaling, which is blocked by TGFβ induced BMP antagonists within the optic fissure margins.

The role of DUBs in the post-translational control of cell migration

2019 ◽  
Vol 63 (5) ◽  
pp. 579-594 ◽  
Author(s):  
Guillem Lambies ◽  
Antonio García de Herreros ◽  
Víctor M. Díaz
Keyword(s):  
Cell Migration ◽  
Translational Control ◽  
Epithelial To Mesenchymal Transition ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Mesenchymal Transition ◽  
Tgfβ Receptors ◽  
Fundamental Process ◽  
Multistep Process

Abstract Cell migration is a multifactorial/multistep process that requires the concerted action of growth and transcriptional factors, motor proteins, extracellular matrix remodeling and proteases. In this review, we focus on the role of transcription factors modulating Epithelial-to-Mesenchymal Transition (EMT-TFs), a fundamental process supporting both physiological and pathological cell migration. These EMT-TFs (Snail1/2, Twist1/2 and Zeb1/2) are labile proteins which should be stabilized to initiate EMT and provide full migratory and invasive properties. We present here a family of enzymes, the deubiquitinases (DUBs) which have a crucial role in counteracting polyubiquitination and proteasomal degradation of EMT-TFs after their induction by TGFβ, inflammatory cytokines and hypoxia. We also describe the DUBs promoting the stabilization of Smads, TGFβ receptors and other key proteins involved in transduction pathways controlling EMT.

scholarly journals The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1239
Author(s):  
Leila Jahangiri ◽  
Tala Ishola ◽  
Perla Pucci ◽  
Ricky M. Trigg ◽  
Joao Pereira ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Progression ◽  
Regulatory Networks ◽  
Epithelial To Mesenchymal Transition ◽  
Tumour Microenvironment ◽  
Repair Capacity ◽  
Mesenchymal Transition ◽  
Cellular Processes

Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, epithelial-to-mesenchymal transition (EMT), and signalling pathways.

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