Plakophilin 2 Couples Actomyosin Remodeling to Desmosomal Plaque Assembly via RhoA

Godsel, Lisa M.; Dubash, Adi D.; Bass-Zubek, Amanda E.; Amargo, Evangeline V.; Klessner, Jodi L.; Hobbs, Ryan P.; Chen, Xinyu; Green, Kathleen J.

doi:10.1091/mbc.e10-02-0131

Cited by 92 publications

(120 citation statements)

References 71 publications

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“…There is evidence that the translocation of cytoplasmic non-membrane bound desmoplakincontaining particles to desmosomes is an actin-dependent process (Godsel et al, 2005). One possible mechanism whereby Rnd3 might regulate desmosomes is through RhoA-dependent regulation of the actin cytoskeleton and activation of RhoA has been shown to accelerate the initial translocation of desmoplakin I/II to desmosomes, although sustained RhoA activity compromised desmosomal maturation (Godsel et al, 2010). Consistent with this, inhibition of RhoA results in loss of desmosomes and keratinocyte dissociation (Waschke et al, 2006).…”

Section: Loss Of Rnd3 Expression Is Associated With Altered Colony Momentioning

confidence: 87%

“…Rnd3 is known to regulate RhoA activity through p190RhoGAP and the RhoA GEF Syx (Wennerberg et al, 2003;Goh and Manser, 2010). RhoA activity during the redistribution of desmoplakin I/II to desmosomes is not affected by p190RhoGAP (Godsel et al, 2010) but this still leaves the possibility that Rnd3 is regulating RhoA through Syx or through some unknown Rnd3 effector.…”

Section: Loss Of Rnd3 Expression Is Associated With Altered Colony Momentioning

confidence: 99%

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Plakoglobin-dependent regulation of keratinocyte APOPTOSIS by Rnd3

Ryan

Lock

Heath

et al. 2012

Journal of Cell Science

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SummaryThe human epidermis is a self-renewing, stratified epithelial tissue that provides the protective function of the skin. The principal cell type within the epidermis is the keratinocyte, and normal function of the epidermis requires that keratinocyte proliferation, differentiation and cell death be carefully controlled. There is clear evidence that signalling through adhesion receptors such as integrins and cadherins plays a key role in regulating epidermal function. Previous work has shown that Rho family GTPases regulate cadherinand integrin-based adhesion structures and hence epidermal function. In this study, we show that a member of this family, Rnd3, regulates desmosomal cell-cell adhesion in that loss of Rnd3 expression leads to an increase in desmosomes at sites of cell-cell adhesion and altered colony morphology. Loss of Rnd3 expression is also associated with resistance to cisplatin-mediated apoptosis in keratinocytes and this resistance is mediated through the desmosomal protein plakoglobin. We propose a novel plakoglobin-dependent role for Rnd3 in the regulation of keratinocyte cell death.

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Section: Loss Of Rnd3 Expression Is Associated With Altered Colony Momentioning

confidence: 87%

Section: Loss Of Rnd3 Expression Is Associated With Altered Colony Momentioning

confidence: 99%

Plakoglobin-dependent regulation of keratinocyte APOPTOSIS by Rnd3

Ryan

Lock

Heath

et al. 2012

Journal of Cell Science

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“…This suggests that RhoA is involved in regulating not only adherens junctions but also in desmosome assembly. PKP2 was shown to regulate cortical actin rearrangement during junction formation (Godsel et al, 2010). These authors showed that in PKP2 knockdown cells activated RhoA failed to localize at intercellular interfaces after the cell -cell contact induction, implicating a role of PKP2 in the spatiotemporal control of RhoA during junction formation (Figure 2).…”

Section: Rho-signalingmentioning

confidence: 97%

Plakophilins in Desmosomal Adhesion and Signaling

Hatzfeld

Wolf

Keil

2014

Cell Communication & Adhesion

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The regulation of adhesion and growth is important for epithelial function and dysfunction. β -catenin ( armadillo in Drosophila ) is the prototype of a multifunctional molecule that regulates cell adhesion via adherens junctions and cell signaling via LEF/TCF transcription factors. Desmosomal armadillo proteins comprise plakoglobin and the plakophilins 1, 2, and 3. These proteins are essential for building up the desmosome and linking the desmosomal cadherins to keratin fi laments. High expression of plakophilins in desmosomes correlates with strong intercellular cohesion and is essential for tissue integrity under mechanical stress. However, like β -catenin, these proteins have diverse non-desmosomal functions, for example, in regulating actin organization, protein synthesis, and growth control. In line with these functions, their de-regulated expression with up-as well as down-regulation has been connected to cancer and metastasis. Now, recent evidence sheds light on the post-translational regulation and provides an explanation for how de-regulation of plakophilins can contribute to cancer.

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“…The relocation of this complex to the membrane requires a properly organized actin cytoskeleton (Figure 2). In this context, RhoA localization at the site of developing desmosomes is necessary, which again is dependent on Pkp2 (Godsel et al, 2010).…”

Section: Mechanisms Regulating Desmosome Turnovermentioning

confidence: 99%

Desmosomal Cadherins and Signaling: Lessons from Autoimmune Disease

Spindler¹,

Waschke²

2014

Cell Communication & Adhesion

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Autoantibodies from patients suffering from the autoimmune blistering skin disease pemphigus can be applied as tools to study desmosomal adhesion. These autoantibodies targeting the desmosomal cadherins desmoglein (Dsg) 1 and Dsg3 cause disruption of desmosomes and loss of intercellular cohesion. Although pemphigus autoantibodies were initially proposed to sterically hinder desmosomes, many groups have shown that they activate signaling pathways which cause disruption of desmosomes and loss of intercellular cohesion by uncoupling the desmosomal plaque from the intermediate fi lament cytoskeleton and/or by interfering with desmosome turnover. These studies demonstrate that desmogleins serve as receptor molecules to transmit outside-in signaling and demonstrate that desmosomal cadherins have functions in addition to their adhesive properties. Two central molecules regulating cytoskeletal anchorage and desmosome turnover are p38MAPK and PKC. As cytoskeletal uncoupling in turn enhances Dsg3 depletion from desmosomes, both mechanisms reinforce one another in a vicious cycle that compromise the integrity and number of desmosomes.

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Plakophilin 2 Couples Actomyosin Remodeling to Desmosomal Plaque Assembly via RhoA

Abstract: The desmosomal armadillo protein plakophilin 2 (PKP2) regulates cell contact-initiated cortical actin remodeling through the regulation of RhoA localization and activity to couple adherens junction maturation with desmosomal plaque assembly.

Cited by 92 publications

References 71 publications

Plakoglobin-dependent regulation of keratinocyte APOPTOSIS by Rnd3

Plakoglobin-dependent regulation of keratinocyte APOPTOSIS by Rnd3

Plakophilins in Desmosomal Adhesion and Signaling

Desmosomal Cadherins and Signaling: Lessons from Autoimmune Disease

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