Signaling of Mechanical Stretch in Human Keratinocytes via MAP Kinases

Kippenberger, Stefan; Bernd, August; Loitsch, Stefan; Guschel, Maike; Müller, Jürgen; Bereiter‐Hahn, Jürgen; Kaufmann, Roland

doi:10.1046/j.1523-1747.2000.00915.x

Cited by 122 publications

(126 citation statements)

References 32 publications

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“…The molecular mechanisms that regulate KRT9 expression remain largely unknown, although pressure and mitogen-activated protein kinase signaling contribute. 12,13 Until now, it was assumed that KRT9 expression was mostly under the control of site-specific volar fibroblasts. Indeed, despite a mixed primary literature, 33e37 it has been commonly hypothesized that primary signals from fibroblasts exclusively dictate epidermal skin identity through epithelial-mesenchymal interactions.…”

Section: Discussionmentioning

confidence: 99%

“…KRT9 can be activated by pressure-activating mitogen-activated protein kinases. 12,13 To further study the mechanism of KRT9 regulation, Moll et al 14 reported that volar fibroblasts induce ectopic nonvolar KRT9 expression in keratinocytes, as rarely is the case in vivo. Grafting of human volar fibroblasts together with nonvolar keratinocytes generated thickened KRT9 þ human epidermis on severe combined immunodeficiency mice.…”

mentioning

confidence: 99%

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To Control Site-Specific Skin Gene Expression, Autocrine Mimics Paracrine Canonical Wnt Signaling and Is Activated Ectopically in Skin Disease

Kim¹,

Hossain²,

Nieves³

et al. 2016

The American Journal of Pathology

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Despite similar components, the heterogeneity of skin characteristics across the human body is enormous. It is classically believed that site-specific fibroblasts in the dermis control postnatal skin identity by modulating the behavior of the surface-overlying keratinocytes in the epidermis. To begin testing this hypothesis, we characterized the gene expression differences between volar (ventral; palmoplantar) and nonvolar (dorsal) human skin. We show that KERATIN 9 (KRT9) is the most uniquely enriched transcript in volar skin, consistent with its etiology in genetic diseases of the palms and soles. In addition, ectopic KRT9 expression is selectively activated by volar fibroblasts. However, KRT9 expression occurs in the absence of all fibroblasts, although not to the maximal levels induced by fibroblasts. Through gain-of-function and loss-of-function experiments, we demonstrate that the mechanism is through overlapping paracrine or autocrine canonical WNTeb-catenin signaling in each respective context. Finally, as an in vivo example of ectopic expression of KRT9 independent of volar fibroblasts, we demonstrate that in the human skin disease lichen simplex chronicus, WNT5a and KRT9 are robustly activated outside of volar sites. These results highlight the complexities of site-specific gene expression and its disruption in skin disease. Site-specific epidermal differentiation programs define the heterogeneity of skin identity across the human body. It is generally believed that positional skin identity is regulated by epithelial (keratinocytes) and mesenchymal (fibroblasts) interactions. 1e5 Indeed, three-dimensional skin equivalent models and transplantation experiments show that epidermal stratification during the keratinocyte differentiation program is remarkably disrupted in the absence of fibroblasts, 2,4,5 demonstrating that epidermal development and homeostasis are regulated by extrinsic factors released by fibroblasts. Such interactions have been further clarified through an analysis of the differential localization of epidermal keratins in distinct epidermal layers and body sites. Volar (palmoplantar) skin is characterized by thick epidermal layers, less pigmentation, and lack of hair. In addition to these features, cytoskeleton KERATIN (KRT) 9 6 has been thought to be almost exclusively localized to volar keratinocytes, 1,6e9 indicating that KRT9 can be a unique marker for volar skin. To date, many clinical studies have reported that KRT9 mutations cause epidermolytic palmoplantar keratoderma, characterized by compensatory thickened epidermal layers in the palms and soles. 10 Conditional deletion of Krt9 in a murine model demonstrated that Krt9 is responsible for maintaining mechanical integrity and terminal differentiation of volar skin.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

To Control Site-Specific Skin Gene Expression, Autocrine Mimics Paracrine Canonical Wnt Signaling and Is Activated Ectopically in Skin Disease

Kim¹,

Hossain²,

Nieves³

et al. 2016

The American Journal of Pathology

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“…Microarray analysis performed on mechanical stretched and normal human skin revealed an up-regulation of AP-1 in mechanically stretched skin (Yang et al 2011). Other stimuli of AP-1 include growth factor signaling via mitogen-activated protein (MAP) kinases, which are also activated in response to mechanical stress (Kippenberger et al 2000). AP-1 acts as a homodimeric or heterodimeric transcription factor composed of members of the Fos (c-Fos, FosB, Fra-1, and Fra-2) and Jun (c-Jun, JunB, and JunD) families.…”

Section: Mechanosensitive Signaling Pathways In the Control Of Desmosmentioning

confidence: 99%

“…Exposure of keratinocytes to stretch results in rapid and transient induction of MAPK ERK1/2 and SAP kinases (Kippenberger et al 2000;Yano et al 2004), accompanied by altered keratin expression, increased keratin phosphorylation and reorganization of keratin networks (Yano et al 2004;Snider and Omary 2014). At least in keratinocytes, mechanical stretching acts via induction of calcium influx, EGFR phosphorylation, and ERK1/2 activation (Yano et al 2004).…”

Section: Impact Of Mechanical Stretch On the Desmosome -Keratin Complexmentioning

confidence: 99%

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

Hatzfeld

Keil

Magin

2017

Cold Spring Harb Perspect Biol

116

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Adherens junctions (AJs) and desmosomes connect the actin and keratin filament networks of adjacent cells into a mechanical unit. Whereas AJs function in mechanosensing and in transducing mechanical forces between the plasma membrane and the actomyosin cytoskeleton, desmosomes and intermediate filaments (IFs) provide mechanical stability required to maintain tissue architecture and integrity when the tissues are exposed to mechanical stress. Desmosomes are essential for stable intercellular cohesion, whereas keratins determine cell mechanics but are not involved in generating tension. Here, we summarize the current knowledge of the role of IFs and desmosomes in tissue mechanics and discuss whether the desmosome-keratin scaffold might be actively involved in mechanosensing and in the conversion of chemical signals into mechanical strength.

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“…The classical ligand for integrins on fibroblasts is fibronectin, which contains the integrin-recognition sequence RGD (31). Specific integrin blocking antibodies or RGD peptides have been widely used to verify involvement of integrins in mechanotransduction (32)(33)(34)(35). To determine whether integrins could mediate the signaling events in response to acoustic pulsed energy, skin fibroblasts were treated with an integrin ␤ 1 blocking antibody…”

Section: Fig 1 Us Induces Increase In Cell Proliferation Of Human Smentioning

confidence: 99%

Molecular Mechanisms of Low Intensity Pulsed Ultrasound in Human Skin Fibroblasts

Zhou

Schmelz

Seufferlein

et al. 2004

Journal of Biological Chemistry

232

168

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Soluble factors such as polypeptide growth factors, mitogenic lipids, inflammatory cytokines, and hormones are known regulators of cell proliferation. However, the effect of mechanical stimuli on cell proliferation is less well understood. Here we examined the effect of low intensity pulsed ultrasound (US), which is used to promote wound healing, on the proliferation of primary human foreskin fibroblasts and the underlying signaling mechanisms. We show that a single 6 -11-min US stimulation increases bromodeoxyuridine incorporation. In addition, an increase in the total cell number is observed after sequential US stimulation. US induced stress fiber and focal adhesion formation via activation of Rho. We further observed that US selectively induced activation of extracellular signal-regulated kinase (ERK) 1/2. Inhibition of Rho-associated coiled-coil-containing protein kinase (ROCK) prevented US-induced ERK1/2 activation, demonstrating that the Rho/ROCK pathway is an upstream regulator of ERK activation in response to US. Consequently, activation of ROCK and MEK-1 was required for US-induced DNA synthesis. Finally, an integrin ␤ 1 blocking antibody as well as a RGD peptide prevented US-induced DNA synthesis. In addition, US slightly increased phosphorylation of Src at Tyr 416 , and Src activity was found to be required for ERK1/2 activation in response to US. In conclusion, our data demonstrate for the first time that US promotes cell proliferation via activation of integrin receptors and a Rho/ROCK/Src/ERK signaling pathway.Signal transduction mechanisms of receptor tyrosine kinase or heptahelical receptors have been studied extensively over the last years. However, the effect of acoustic pulsed energy on cell growth and the signal transduction mechanisms induced by this type of mechanical stimulation are not well understood. Previous studies have shown that mechanical stress such as stretch and shear stress can induce DNA synthesis in certain cell types and that extracellular signal-regulated kinase (ERK) 1 1/2 can be activated by mechanical stress (1-4).Low intensity pulsed ultrasound (US) is a special type of acoustic pulsed energy that is increasingly used as a supplementary therapy to promote bone and wound healing (5). US, transmitting as an acoustic pressure wave and applying mechanical stress indirectly to the tissues, has been reported to promote osteogenesis and protein synthesis, calcium uptake, and DNA synthesis in different cells (6 -9). US-induced DNA synthesis seems cell type-dependent; US promotes DNA synthesis in human osteoblasts, gingival fibroblasts, and periosteal cells (6, 8, 10), but not in chondrocytes (11,12). However, the molecular mechanisms by which US induces DNA synthesis or even cell proliferation are largely unknown.There is growing evidence that integrins are promising candidates for sensing extracellular matrix-derived mechanical stimuli and converting them into biochemical signals (13,14). Integrin-associated signaling pathways include an increase in tyrosine phosphorylation of...

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Signaling of Mechanical Stretch in Human Keratinocytes via MAP Kinases

Cited by 122 publications

References 32 publications

To Control Site-Specific Skin Gene Expression, Autocrine Mimics Paracrine Canonical Wnt Signaling and Is Activated Ectopically in Skin Disease

To Control Site-Specific Skin Gene Expression, Autocrine Mimics Paracrine Canonical Wnt Signaling and Is Activated Ectopically in Skin Disease

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

Molecular Mechanisms of Low Intensity Pulsed Ultrasound in Human Skin Fibroblasts

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