The desmoplakin–intermediate filament linkage regulates cell mechanics

Broussard, Joshua A.; Yang, Ruiguo; Huang, Changjin; Nathamgari, S. Shiva P.; Beese, Allison M.; Godsel, Lisa M.; Hegazy, Marihan; Sherry, Lance; Zhang, Fan; Sniadecki, Nathan J.; Green, Kathleen J.; Espinosa, Horacio D.

doi:10.1091/mbc.e16-07-0520

Cited by 73 publications

(100 citation statements)

References 51 publications

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“…This evidence lends support to the notion that abundant molecular communication exists between the two mechanically active junctional complexes [117]. The same study showed that the desmosome/IF linkage has a significant impact on global cell mechanics as well as tension within the cell–cell interface [21]. Different forms of DP were expressed in A431 cell lines to investigate the role of this linkage in regulating cell mechanics.…”

Section: Techniques To Study Cell–cell Adhesionsupporting

confidence: 53%

“…However, removing the keratin IF system was shown to affect the mechanical properties of cells as well as their ability to migrate [20]. Moreover, manipulating the strength of the desmosome/IF linkage using DP mutants regulates both intercellular forces in cell pairs and cell stiffness in cell pairs and larger groups of cells, through a process involving the actin cytoskeleton [21]. …”

Section: Cell–cell Adhesion Complexesmentioning

confidence: 99%

“…In a recent study, the desmosome/IF linkage at cell–cell junctions has also been shown to regulate not only traction forces at cell–ECM adhesions, but also modulate forces at cell–cell junctions [21]. Using a combined approach of micropost arrays and AFM, epithelial cells with genetic mutation of a desmosome/IF linker molecule, DP, which lacks the IF-binding domain, exhibited significantly reduced traction forces and potentially increased tension or conformational changes in α -catenin of AJs [21,116]. This evidence lends support to the notion that abundant molecular communication exists between the two mechanically active junctional complexes [117].…”

Section: Techniques To Study Cell–cell Adhesionmentioning

confidence: 99%

“…These results suggest that changes at the cell–cell adhesion complex have a major impact on global cell mechanics. In addition, the stiffness changes observed on cells with DP mutations can be abrogated by depolymerizing actin filaments, indicating a potential crosstalk between the desmosome/IF and AJ/actin filament networks [21]. Furthermore, considering the significant difference in the mechanical properties of the cytoskeleton and the cytosol, AFM images obtained by applying a small force to the cell can reveal the cytoskeleton structures at the cell–cell adhesion junction as shown in Fig.…”

Section: Techniques To Study Cell–cell Adhesionmentioning

confidence: 99%

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Techniques to stimulate and interrogate cell–cell adhesion mechanics

Yang

Broussard

Green

et al. 2018

Extreme Mechanics Letters

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Cell–cell adhesions maintain the mechanical integrity of multicellular tissues and have recently been found to act as mechanotransducers, translating mechanical cues into biochemical signals. Mechanotransduction studies have primarily focused on focal adhesions, sites of cell-substrate attachment. These studies leverage technical advances in devices and systems interfacing with living cells through cell–extracellular matrix adhesions. As reports of aberrant signal transduction originating from mutations in cell–cell adhesion molecules are being increasingly associated with disease states, growing attention is being paid to this intercellular signaling hub. Along with this renewed focus, new requirements arise for the interrogation and stimulation of cell–cell adhesive junctions. This review covers established experimental techniques for stimulation and interrogation of cell–cell adhesion from cell pairs to monolayers.

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Section: Techniques To Study Cell–cell Adhesionsupporting

confidence: 53%

Section: Cell–cell Adhesion Complexesmentioning

confidence: 99%

Section: Techniques To Study Cell–cell Adhesionmentioning

confidence: 99%

Section: Techniques To Study Cell–cell Adhesionmentioning

confidence: 99%

See 2 more Smart Citations

Techniques to stimulate and interrogate cell–cell adhesion mechanics

Yang

Broussard

Green

et al. 2018

Extreme Mechanics Letters

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“…This mutant, referred to as DPNTP ( Figure 1A), consists of the first 584 amino acids of DP. It retains the ability to interact with the desmosomal core but lacks the IF-binding domains, acting as a dominant negative mutant to uncouple desmosomes from the IF network [14][15][16]. We previously showed that expression of the uncoupling mutant in a simple epithelial A431 cell model (an epidermoid cell line) results in retraction of the IF cytoskeleton from sites of cell-cell adhesion [14].…”

Section: Uncoupling the Desmosome/if Connection Induces Rearrangementmentioning

confidence: 99%

Desmosomes polarize mechanical signaling to govern epidermal tissue form and function

Broussard¹,

Koetsier²,

Hegazy³

et al. 2020

Preprint

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The epidermis is a stratified epithelium in which structural and functional features are polarized across multiple cell layers. This type of polarity is essential for establishing the epidermal barrier, but how it is created and sustained is poorly understood. Previous work identified a role for the classical cadherin/filamentous-actin network in establishment of epidermal polarity. However, little is known about potential roles of the most prominent epidermal intercellular junction, the desmosome, in establishing epidermal polarity, in spite of the fact that desmosome constituents are patterned across the apical to basal cell layers. Here, we show that desmosomes and their associated intermediate filaments (IF) are key regulators of mechanical polarization in epidermis, whereby basal and suprabasal cells experience different forces that drive layer-specific functions. Uncoupling desmosomes and IF or specific targeting of apical desmosomes through depletion of the superficial desmosomal cadherin, desmoglein 1, impedes basal (stratification) and suprabasal (tight junction barrier) functions. Surprisingly, disengaging desmosomes from IF also uncouples stratification from differentiation, accelerating the expression of differentiation markers. Our data support a model in which the desmosome-IF network supports a reciprocally organized distribution of ErbB1/EGFR activity in the basal layer and mechanosensitive kinase ErbB2 activity in the suprabasal layer to ensure the proper spatiotemporal coordination of cell mechanics and the biochemical program of differentiation.

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Disruption of desmosome function leads to increased centrosome clustering in 14‐3‐3γ‐knockout cells with supernumerary centrosomes

et al. 2021

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14‐3‐3 proteins are conserved, dimeric, acidic proteins that regulate multiple cellular pathways. Loss of either 14‐3‐3ε or 14‐3‐3γ leads to centrosome amplification. However, we find that while the knockout of 14‐3‐3ε leads to multipolar mitoses, the knockout of 14‐3‐3γ results in centrosome clustering and pseudo‐bipolar mitoses. 14‐3‐3γ knockouts demonstrate compromised desmosome function and a decrease in keratin levels, leading to decreased cell stiffness and an increase in centrosome clustering. Restoration of desmosome function increased multipolar mitoses, whereas knockdown of either plakoglobin or keratin 5 led to decreased cell stiffness and increased pseudo‐bipolar mitoses. These results suggest that the ability of the desmosome to anchor keratin filaments maintains cell stiffness, thus inhibiting centrosome clustering, and that phenotypes observed upon 14‐3‐3 loss reflect the dysregulation of multiple pathways.

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The desmoplakin–intermediate filament linkage regulates cell mechanics

Cited by 73 publications

References 51 publications

Techniques to stimulate and interrogate cell–cell adhesion mechanics

Techniques to stimulate and interrogate cell–cell adhesion mechanics

Desmosomes polarize mechanical signaling to govern epidermal tissue form and function

Disruption of desmosome function leads to increased centrosome clustering in 14‐3‐3γ‐knockout cells with supernumerary centrosomes

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