Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulating YAP and Phospho-YAP in Keratinocyte Responses to Mechanical Forces

Desmoglein 3 (Dsg3) plays a crucial role in cell-cell adhesion and tissue integrity. Increasing evidence suggests that Dsg3 acts as a regulator of cellular mechanotransduction, but little is known about its direct role in mechanical force transmission. The present study investigated the impact of cyclic strain and substrate stiffness on Dsg3 expression and its role in mechanotransduction in keratinocytes. A direct comparison was made with E-cadherin, a well-characterized mechanosensor. Exposure of oral and skin keratinocytes to equiaxial cyclic strain promoted changes in the expression and localization of junction assembly proteins. The knockdown of Dsg3 by siRNA blocked strain-induced junctional remodeling of E-cadherin and Myosin IIa. Importantly, the study demonstrated that Dsg3 regulates the expression and localization of yes-associated protein (YAP), a mechanosensory, and an effector of the Hippo pathway. Furthermore, we showed that Dsg3 formed a complex with phospho-YAP and sequestered it to the plasma membrane, while Dsg3 depletion had an impact on both YAP and phospho-YAP in their response to mechanical forces, increasing the sensitivity of keratinocytes to the strain or substrate rigidity-induced nuclear relocation of YAP and phospho-YAP. Plakophilin 1 (PKP1) seemed to be crucial in recruiting the complex containing Dsg3/phospho-YAP to the cell surface since its silencing affected Dsg3 junctional assembly with concomitant loss of phospho-YAP at the cell periphery. Finally, we demonstrated that this Dsg3/YAP pathway has an influence on the expression of YAP1 target genes and cell proliferation. Together, these findings provide evidence of a novel role for Dsg3 in keratinocyte mechanotransduction.

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The desmosomal cadherin Desmoglein-3 regulates YAP and phospho-YAP in keratinocyte responses to mechanical forces

10.1101/827725 ◽

2019 ◽

Author(s):

Jutamas Uttagomol ◽

Usama Sharif Ahmad ◽

Ambreen Rehman ◽

Yunying Huang ◽

Ana C. Laly ◽

...

Keyword(s):

Target Genes ◽

Hippo Pathway ◽

Cyclic Strain ◽

Human Keratinocytes ◽

Mechanical Forces ◽

Force Transmission ◽

Direct Role ◽

The Impact ◽

Desmoglein 3 ◽

E Cadherin

ABSTRACTDesmoglein 3 (Dsg3), plays a crucial role in cell-cell adhesion and tissue integrity. Increasing evidence suggests that Dsg3 acts as a regulator of cellular mechanotransduction, but little is known about its direct role in mechanical force transmission. The present study investigated the impact of cyclic strain and substrate stiffness on Dsg3 expression and its role in mechanotransduction. A direct comparison was made with E-cadherin, a well-characterized mechanosensor, in human keratinocytes. Exposure of oral and skin keratinocytes to equiaxial cyclic strain promoted changes in expression and localization of junction assembly proteins. Knockdown of Dsg3 by siRNA blocked strain-induced junctional remodeling of E-cadherin and Myosin IIa. Importantly, the study demonstrated that Dsg3 regulates the expression and localization of YAP, a mechanosensor and an effector of the Hippo pathway. Furthermore, we showed that Dsg3 forms a complex with phospho-YAP and sequestered it to the plasma membrane, while Dsg3 depletion had an impact on both YAP and phospho-YAP in their response to mechanical forces, increasing the sensitivity of keratinocytes to both strain-or substrate rigidity-induced nuclear relocalization of YAP and phospho-YAP. We showed that PKP1 seemed to be the key in such a complex formation since its silencing resulted in Dsg3 disruption at the junctions with concomitant loss of pYAP in the peripheral cytoplasm. Finally, we demonstrated that this Dsg3/YAP pathway has an influence on the expression of YAP1 target genes as well as cell proliferation in keratinocytes. Together, these findings provide evidence of a novel role for Dsg3 in keratinocyte mechanotransduction.

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Hippo and rassf1a Pathways: A Growing Affair

Molecular Biology International ◽

10.1155/2012/307628 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 14

Author(s):

Francesca Fausti ◽

Silvia Di Agostino ◽

Andrea Sacconi ◽

Sabrina Strano ◽

Giovanni Blandino

Keyword(s):

Developmental Biology ◽

Tissue Regeneration ◽

Target Genes ◽

Hippo Pathway ◽

Hippo Signaling ◽

Transcriptional Coactivator ◽

Pathway Activity ◽

Kinase Cascade ◽

The Hippo Pathway ◽

The Impact

First discovered in Drosophila, the Hippo pathway regulates the size and shape of organ development. Its discovery and study have helped to address longstanding questions in developmental biology. Central to this pathway is a kinase cascade leading from the tumor suppressor Hippo (Mst1 and Mst2 in mammals) to the Yki protein (YAP and TAZ in mammals), a transcriptional coactivator of target genes involved in cell proliferation, survival, and apoptosis. A dysfunction of the Hippo pathway activity is frequently detected in human cancers. Recent studies have highlighted that the Hippo pathway may play an important role in tissue homoeostasis through the regulation of stem cells, cell differentiation, and tissue regeneration. Recently, the impact of RASSF proteins on Hippo signaling potentiating its proapoptotic activity has been addressed, thus, providing further evidence for Hippo's key role in mammalian tumorigenesis as well as other important diseases.

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Multiple functions of the scaffold protein Discs large 5 in the control of growth, cell polarity and cell adhesion in Drosophila melanogaster

10.21203/rs.3.rs-16603/v2 ◽

2020 ◽

Author(s):

Parvathy Venugopal ◽

Hugo Veyssiere ◽

Jean-Louis Couderc ◽

Graziella Richard ◽

Caroline Vachias ◽

...

Keyword(s):

Cell Adhesion ◽

Cell Size ◽

Cell Polarity ◽

Hippo Pathway ◽

Wing Disc ◽

Animal Development ◽

Discs Large ◽

A Cell ◽

The Impact ◽

E Cadherin

Abstract Background : Scaffold proteins support a variety of key processes during animal development. Mutant mouse for the MAGUK protein Discs large 5 (Dlg5) presents a general growth impairment and moderate morphogenetic defects. Results: Here, we generated null mutants for Drosophila Dlg5 and show that it owns similar functions in growth and epithelial architecture. Dlg5 is required for growth at a cell autonomous level in several tissues and at the organism level, affecting cell size and proliferation. Our results are consistent with Dlg5 modulating hippo pathway in the wing disc, including the impact on cell size, a defect that is reproduced by the loss of yorkie. However, other observations indicate that Dlg5 regulates growth by at least another way that may involve Myc protein but nor PI3K neither TOR pathways. Moreover, epithelia cells mutant for Dlg5 also show a reduction of apical domain determinants, though not sufficient to induce a complete loss of cell polarity. Dlg5 is also essential, in the same cells, for the presence at Adherens junctions of N-Cadherin, but not E-Cadherin. Genetic analyses indicate that junction and polarity defects are independent. Conclusions : Together our data show that Dlg5 own several conserved functions that are independent of each other in regulating growth, cell polarity and cell adhesion. Moreover, they reveal a differential regulation of E-cadherin and N-cadherin apical localization.

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Multiple functions of the scaffold protein Discs large 5 in the control of growth, cell polarity and cell adhesion in Drosophila melanogaster

10.21203/rs.3.rs-16603/v3 ◽

2020 ◽

Author(s):

Parvathy Venugopal ◽

Hugo Veyssiere ◽

Jean-Louis Couderc ◽

Graziella Richard ◽

Caroline Vachias ◽

...

Keyword(s):

Cell Adhesion ◽

Cell Size ◽

Cell Polarity ◽

Hippo Pathway ◽

Wing Disc ◽

Animal Development ◽

Discs Large ◽

A Cell ◽

The Impact ◽

E Cadherin

Abstract Background : Scaffold proteins support a variety of key processes during animal development. Mutant mouse for the MAGUK protein Discs large 5 (Dlg5) presents a general growth impairment and moderate morphogenetic defects. Results : Here, we generated null mutants for Drosophila Dlg5 and show that it owns similar functions in growth and epithelial architecture. Dlg5 is required for growth at a cell autonomous level in several tissues and at the organism level, affecting cell size and proliferation. Our results are consistent with Dlg5 modulating hippo pathway in the wing disc, including the impact on cell size, a defect that is reproduced by the loss of yorkie. However, other observations indicate that Dlg5 regulates growth by at least another way that may involve Myc protein but nor PI3K neither TOR pathways. Moreover, epithelia cells mutant for Dlg5 also show a reduction of apical domain determinants, though not sufficient to induce a complete loss of cell polarity. Dlg5 is also essential, in the same cells, for the presence at Adherens junctions of N-Cadherin, but not E-Cadherin. Genetic analyses indicate that junction and polarity defects are independent. Conclusions : Together our data show that Dlg5 own several conserved functions that are independent of each other in regulating growth, cell polarity and cell adhesion. Moreover, they reveal a differential regulation of E-cadherin and N-cadherin apical localization.

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The Tip of an Iceberg: Replication-Associated Functions of the Tumor Suppressor p53

Cancers ◽

10.3390/cancers10080250 ◽

2018 ◽

Vol 10 (8) ◽

pp. 250 ◽

Cited By ~ 7

Author(s):

Vanesa Gottifredi ◽

Lisa Wiesmüller

Keyword(s):

Dna Replication ◽

Tumor Suppressor ◽

Target Genes ◽

Data Sets ◽

Replication Forks ◽

Tumor Suppressor P53 ◽

Direct Role ◽

Associated Functions ◽

The Impact

The tumor suppressor p53 is a transcriptional factor broadly mutated in cancer. Most inactivating and gain of function mutations disrupt the sequence-specific DNA binding domain, which activates target genes. This is perhaps the main reason why most research has focused on the relevance of such transcriptional activity for the prevention or elimination of cancer cells. Notwithstanding, transcriptional regulation may not be the only mechanism underlying its role in tumor suppression and therapeutic responses. In the past, a direct role of p53 in DNA repair transactions that include the regulation of homologous recombination has been suggested. More recently, the localization of p53 at replication forks has been demonstrated and the effect of p53 on nascent DNA elongation has been explored. While some data sets indicate that the regulation of ongoing replication forks by p53 may be mediated by p53 targets such as MDM2 (murine double minute 2) and polymerase (POL) eta other evidences demonstrate that p53 is capable of controlling DNA replication by directly interacting with the replisome and altering its composition. In addition to discussing such findings, this review will also analyze the impact that p53-mediated control of ongoing DNA replication has on treatment responses and tumor suppressor abilities of this important anti-oncogene.

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Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

International Journal of Molecular Sciences ◽

10.3390/ijms22083955 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3955

Author(s):

László Bálint ◽

Zoltán Jakus

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Cell Fate ◽

Molecular Mechanisms ◽

Critical Role ◽

Mechanical Forces ◽

Lymphatic Endothelial Cells ◽

Lymphatic Development ◽

And Function ◽

The Impact

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

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The Impact of Mechanical Forces in Heart Morphogenesis

Circulation Cardiovascular Genetics ◽

10.1161/circgenetics.111.961086 ◽

2012 ◽

Vol 5 (1) ◽

pp. 132-142 ◽

Cited By ~ 47

Author(s):

Javier T. Granados-Riveron ◽

J. David Brook

Keyword(s):

Mechanical Forces ◽

Heart Morphogenesis ◽

The Impact

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Cell Fitness: More Than Push-Ups

International Journal of Molecular Sciences ◽

10.3390/ijms22020518 ◽

2021 ◽

Vol 22 (2) ◽

pp. 518

Author(s):

Adam James Ferrari ◽

Ronny Drapkin ◽

Rajan Gogna

Keyword(s):

Cancer Progression ◽

Hippo Pathway ◽

Cancer Therapeutics ◽

Protein Isoforms ◽

Cell Junction ◽

Cell Competition ◽

Molecular Features ◽

Oncogenic Pathways ◽

Diagnostic Potential ◽

The Impact

Cell competition (CC) is a feature that allows tumor cells to outcompete and eliminate adjacent cells that are deemed less fit. Studies of CC, first described in Drosophila melanogaster, reveal a diversity of underlying mechanisms. In this review, we will discuss three recent studies that expand our understanding of the molecular features governing CC. In particular, we will focus on a molecular fitness fingerprint, oncogenic pathways, and the importance of cell junction stability. A fitness fingerprint, mediated by flower (hFWE) protein isoforms, dictates that cells expressing the flower-win isoforms will outcompete adjacent flower-loss-expressing cells. The impact of the flower protein isoforms is seen in cancer progression and may have diagnostic potential. The yes-associated protein (YAP) and TAZ transcription factors, central mediators of the oncogenic Hippo pathway, elevate peritumoral fitness thereby protecting against tumor progression and provide a suppressive barrier. Similarly, COL17A1 is a key component in hemidesmosome stability, and its expression in epidermal stem cells contributes to fitness competition and aging characteristics. The contributions of these pathways to disease development and progression will help define how CC is hijacked to favor cancer growth. Understanding these features will also help frame the diagnostic and therapeutic possibilities that may place CC in the crosshairs of cancer therapeutics.

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Analysis on Force Transmission Characteristics of Two-Legged Shield Support under Impact Loading

Shock and Vibration ◽

10.1155/2018/3854684 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Qing-liang Zeng ◽

Zhao-sheng Meng ◽

Li-rong Wan ◽

Cheng-long Wang

Keyword(s):

Structural Design ◽

Load Transfer ◽

Impact Load ◽

Force Transmission ◽

Full Account ◽

Flexible Bodies ◽

Powered Support ◽

Structural Design Optimization ◽

Hinge Points ◽

The Impact

To study the load transfer characteristics of a two-legged shield powered support, a numerical simulation model of the support was established using the multibody dynamics software ADAMS. The model took full account of the hydraulic-elastic deformation characteristics of the support, as a series spring-damper system was used to replace the leg and the equilibrium jack. The canopy, goaf shield, lemniscate bars, and equilibrium jack are equivalent to flexible bodies. The setting force of the leg was provided by the preload of the equivalent spring, the static roof load was simulated using a slope signal, and the impact load was simulated using a step signal. Using the model, the impact and excitation effects of each hinge joint of the support were analyzed under different impact load conditions across the canopy. The results show that the location of the impact load affects the force transmissions of all hinge points of the support. Both the impact effect and the excitation effect are at a minimum when the impact force is located near the leg action line. These results are useful for the adaptive control and structural design optimization of the support.

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Identification of anticancer drug target genes using an outside competitive dynamics model on cancer signaling networks

Scientific Reports ◽

10.1038/s41598-021-93336-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tien-Dzung Tran ◽

Duc-Tinh Pham

Keyword(s):

Anticancer Drug ◽

Drug Target ◽

Target Genes ◽

Signaling Network ◽

Competitive Dynamics ◽

Signaling Networks ◽

Molecular Signaling ◽

Dynamics Model ◽

Cancer Signaling ◽

The Impact

AbstractEach cancer type has its own molecular signaling network. Analyzing the dynamics of molecular signaling networks can provide useful information for identifying drug target genes. In the present study, we consider an on-network dynamics model—the outside competitive dynamics model—wherein an inside leader and an opponent competitor outside the system have fixed and different states, and each normal agent adjusts its state according to a distributed consensus protocol. If any normal agent links to the external competitor, the state of each normal agent will converge to a stable value, indicating support to the leader against the impact of the competitor. We determined the total support of normal agents to each leader in various networks and observed that the total support correlates with hierarchical closeness, which identifies biomarker genes in a cancer signaling network. Of note, by experimenting on 17 cancer signaling networks from the KEGG database, we observed that 82% of the genes among the top 3 agents with the highest total support are anticancer drug target genes. This result outperforms those of four previous prediction methods of common cancer drug targets. Our study indicates that driver agents with high support from the other agents against the impact of the external opponent agent are most likely to be anticancer drug target genes.

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