Epidermal RAF prevents allergic skin disease

Raguz, Josipa; Jeric, Ines; Niault, Théodora; Nowacka, Joanna; Kuzet, Sanya Eduarda; Rupp, Christian; Fischer, Ilse; Biggi, Silvia; Borsello, Tiziana; Baccarini, Manuela

doi:10.7554/elife.14012

Cited by 14 publications

(9 citation statements)

References 67 publications

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“…The residual ERK phosphorylation in BRAF D/D /RAF1 D/D pMECs does not correlate with ARAF upregulation (data not shown). A similar phenotype has been observed in primary keratinocytes [31][32][33], and may be due to the activity of alternative MEK kinases, such as TPL2 or MOS, due to reduced DUSP expression, or due to the attenuation of ERK-dependent negative feedback mechanisms.…”

Section: Raf1 Ablation Rescues the Permeability Defects Of Braf-deficsupporting

confidence: 64%

RAF dimers control vascular permeability and cytoskeletal rearrangements at endothelial cell‐cell junctions

et al. 2019

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The endothelium functions as a semipermeable barrier regulating fluid homeostasis, nutrient, and gas supply to the tissue. Endothelial permeability is increased in several pathological conditions including inflammation and tumors; despite its clinical relevance, however, there are no specific therapies preventing vascular leakage. Here, we show that endothelial cell‐restricted ablation of BRAF , a kinase frequently activated in cancer, prevents vascular leaking as well metastatic spread. BRAF regulates endothelial permeability by promoting the cytoskeletal rearrangements necessary for the remodeling of VE ‐Cadherin‐containing endothelial cell–cell junctions and the formation of intercellular gaps. BRAF kinase activity and the ability to form complexes with RAS / RAP 1 and dimers with its paralog RAF 1 are required for proper permeability control, achieved mechanistically by modulating the interaction between RAF 1 and the RHO effector ROK α. Thus, RAF dimerization impinges on RHO pathways to regulate cytoskeletal rearrangements, junctional plasticity, and endothelial permeability. The data advocate the development of RAF dimerization inhibitors, which would combine tumor cell autonomous effect with stabilization of the vasculature and antimetastatic spread.

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Section: Raf1 Ablation Rescues the Permeability Defects Of Braf-deficsupporting

confidence: 64%

RAF dimers control vascular permeability and cytoskeletal rearrangements at endothelial cell‐cell junctions

et al. 2019

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“…Primary mouse keratinocytes, epidermal lysates and HaCat cells54, immortalized endothelial cells55 and mouse embryonic fibroblasts (MEFs)9 were obtained and cultured as described. Human HCC lines were obtained from Wolfgang Mikulits (Institute of Cancer Research, Medical University of Vienna—verified by STR analysis) and cultured in DMEM or RPMI (HepG2) supplemented with 10% FBS and 1% penicillin–streptomycin.…”

Section: Methodsmentioning

confidence: 99%

A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis

et al. 2016

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Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, but its molecular heterogeneity hampers the design of targeted therapies. Currently, the only therapeutic option for advanced HCC is Sorafenib, an inhibitor whose targets include RAF. Unexpectedly, RAF1 expression is reduced in human HCC samples. Modelling RAF1 downregulation by RNAi increases the proliferation of human HCC lines in xenografts and in culture; furthermore, RAF1 ablation promotes chemical hepatocarcinogenesis and the proliferation of cultured (pre)malignant mouse hepatocytes. The phenotypes depend on increased YAP1 expression and STAT3 activation, observed in cultured RAF1-deficient cells, in HCC xenografts, and in autochthonous liver tumours. Thus RAF1, although essential for the development of skin and lung tumours, is a negative regulator of hepatocarcinogenesis. This unexpected finding highlights the contribution of the cellular/tissue environment in determining the function of a protein, and underscores the importance of understanding the molecular context of a disease to inform therapy design.

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“…Epidermal development, homeostasis, and repair are complex processes requiring regulation of cell proliferation, migration, and differentiation. Several of the signals essential for epidermal development and repair are tranduced by the epidermal growth factor receptor (EGFR) and integrins [51]. Two genes were represented in the cellular enzyme and receptor activity term of the category molecular function, (23) RAF1 and (24) ROCK1 ( Table 7).…”

Section: Go Term Group -Cellular Enzyme and Receptor Activitymentioning

confidence: 99%

The identification of gene ontologies and candidate genes for digital dermatitis in beef cattle from a genome-wide association study

Kopke¹,

Anklam²,

Kulow³

et al. 2020

Int J Vet Sci Res

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Bovine Digital Dermatitis (DD) is an infectious disease causing severe lameness in cattle. The aim of this study was to perform a Genome Wide Association Study (GWAS) and a Gene-Set Enrichment Analysis (GSEA) to identify candidate genes, instead of an individual Single Nucleotide Polymorphism (SNP), associated with DD traits in beef cattle. Beef cattle (n= 307) were genotyped with the Illumina GGP-HD bovine 150K SNP chip. The M-scores of the cattle over the observation period were used to defi ne the DD traits with different complexities, the distinction between affected (1) and unaffected (0) cattle, regarding the general DD-status (DD AFFECTED), acute disease events (DD ACUTE), visible signs of chronicity (DD CHRONICITY) and proliferation of the skin (DD PROLIFERATION). The gene-set enrichment analysis revealed 30 Gene Ontology (GO) terms associated with the DD AFFECTED trait and 17, 31, and 16 GO terms were associated with DD ACUTE, DD CHRONICITY, and DD PROLIFERATION traits, respectively. By searching the signifi cantly enriched GO terms from the ontology categories, biological process and cellular components, and molecular function, 25 functional genes were identifi ed that were highly involved in cellular and membrane function pertaining to adhesion, migration and proliferation which could contribute to DD traits. These results could provide insight into the genetic framework of this complex trait and disease in beef cattle to aid the development of potential genetic therapies as well as selective breeding strategies to decrease DD prevalence in cattle.

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Epidermal RAF prevents allergic skin disease

Cited by 14 publications

References 67 publications

RAF dimers control vascular permeability and cytoskeletal rearrangements at endothelial cell‐cell junctions

RAF dimers control vascular permeability and cytoskeletal rearrangements at endothelial cell‐cell junctions

A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis

The identification of gene ontologies and candidate genes for digital dermatitis in beef cattle from a genome-wide association study

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