Epidermal growth factor activates β-catenin via integrin-linked kinase to control proliferation of mesenchymal stromal cells.
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ABSTRACT:
PROVIDER: PRJNA498109 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8099000_1.fastq.gz | Fastqsanger.gz | |||
| SRR8099000_2.fastq.gz | Fastqsanger.gz | |||
| SRR8099001_1.fastq.gz | Fastqsanger.gz | |||
| SRR8099001_2.fastq.gz | Fastqsanger.gz | |||
| SRR8099002_1.fastq.gz | Fastqsanger.gz |
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Project description:Mesenchymal stromal cells (MSCs) are located in bone marrow where they help to maintain bone homeostasis and repair through the ability to expand in response to mitotic stimuli and differentiate into skeletal linages. The signalling mechanisms that enable precise control of MSC function remain unclear. Here, we have identified a non-canonical epidermal growth factor (EGF) signalling pathway in MSCs, which acts via integrin-linked kinase (ILK) to activate β-catenin, a key component of Wnt signalling. EGF induces nuclear translocation of β-catenin in MSCs but does not drive T cell factor (TCF)-mediated transactivation of Wnt target genes, and we demonstrate by Design of Experiments statistical analysis that the EGF/β-catenin and Wnt/β-catenin pathways do not cross-talk following co-stimulation with multiple concentrations of both ligands. By examining EGF-regulated genes in MSCs by RNA-Sequencing, we identified gene sets that were exclusively regulated by the EGF/b-catenin pathway, which were distinct from canonical EGF-regulated genes. In contrast, the expression of subsets of canonical EGF signalling gene targets were significantly influenced by b-catenin activation. These newly-identified EGF signalling pathways cooperate to enable EGF-mediated proliferation of MSCs by alleviating the suppression of cell cycle pathways induced by canonical EGF signalling.
2018-10-24 | GSE121697 | GEO
Project description:Ovarian cancer (OC) is the most lethal gynecological cancer. OC cells have high proliferative capacity, are invasive, resist apoptosis, and tumors often display rearrangement of extracellular matrix (ECM) components, contributing to accelerated tumor progression. The multifunctional protein tissue transglutaminase (TG2) is known to be secreted in the tumor microenvironment, where it interacts with fibronectin (FN) and the cell surface receptor integrin β1. However, the mechanistic role of TG2 in cancer cell proliferation is unknown. Here, we demonstrate that TG2 directly interacts with and facilitates the phosphorylation and activation of the integrin effector protein integrin-linked kinase (ILK) at Ser246. We show that TG2 and p-Ser246-ILK form a complex that is detectable in patient-derived OC primary cells grown on FN-coated slides. In addition, we show that coexpression of TGM2 and ILK correlates with poor clinical outcome. Mechanistically, we demonstrate that TG2-mediated ILK activation causes phosphorylation of glycogen synthase kinase-3α/β, allowing β-catenin nuclear translocation and transcriptional activity. Furthermore, inhibition of TG2 and ILK using small molecules, neutralizing antibodies, or shRNA-mediated knockdown blocks cell adhesion to the FN matrix, as well as the Wnt receptor response to the Wnt-3A ligand, and ultimately, cell adhesion, growth, and migration. In conclusion, we demonstrate that TG2 directly interacts with and activates ILK in OC cells and tumors and define a new mechanism that links ECM cues with β-catenin signaling in OC. These results suggest a central role of TG2-FN-integrin clusters in ECM rearrangement and indicate that downstream effector ILK may represent a potential new therapeutic target in OC.
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Project description:Hair follicle formation depends on reciprocal epidermal-dermal interactions and occurs during skin development, but not in adult life. This suggests that the properties of dermal fibroblasts change during postnatal development. To examine this, we used a PdgfraEGFP mouse line to isolate GFP-positive fibroblasts from neonatal skin, adult telogen and anagen skin and adult skin in which ectopic hair follicles had been induced (EF skin) by transgenic epidermal activation of beta-catenin. We also isolated epidermal cells from each mouse. The gene expression profile of EF epidermis was most similar to that of anagen epidermis, consistent with activation of beta-catenin signalling. In contrast, adult dermis with ectopic hair follicles more closely resembled neonatal dermis than adult telogen or anagen dermis. In particular, genes associated with mitosis were upregulated and extracellular matrix-associated genes were downregulated in neonatal and EF fibroblasts. We confirmed that sustained epidermal beta-catenin activation stimulated fibroblasts to proliferate to reach the high cell density of neonatal skin. In addition, the extracellular matrix was comprehensively remodelled, with mature collagen being replaced by collagen subtypes normally present only in developing skin. The changes in proliferation and extracellular matrix composition originated from a specific subpopulation of fibroblasts located beneath the sebaceous gland. Our results show that adult dermis is an unexpectedly plastic tissue that can be reprogrammed to acquire the molecular, cellular and structural characteristics of neonatal dermis in response to cues from the overlying epidermis. We have isolated the following populations of cells from mouse back skin by flow cytometry: 1A) GFP+ WT neonatal dermal fibroblasts, 1B) ItgA6+ WT neonatal epidermal keratinocytes, 2A) GFP+ WT telogen dermal fibroblasts, 2B) ItgA6+ WT telogen epidermal keratinocytes, 3A) GFP+ D2 transient activation (anagen) dermal fibroblasts, 3B) ItgA6+ D2 transient activation (anagen) epidermal keratinocytes, 4A) GFP+ D2 sustained activation (ectopic follicles) dermal fibroblasts, 4B) ItgA6+ D2 sustained activation (ectopic follicles) epidermal keratinocytes
2011-10-12 | E-GEOD-32966 | biostudies-arrayexpress
Project description:Hair follicle formation depends on reciprocal epidermal-dermal interactions and occurs during skin development, but not in adult life. This suggests that the properties of dermal fibroblasts change during postnatal development. To examine this, we used a PdgfraEGFP mouse line to isolate GFP-positive fibroblasts from neonatal skin, adult telogen and anagen skin and adult skin in which ectopic hair follicles had been induced (EF skin) by transgenic epidermal activation of beta-catenin. We also isolated epidermal cells from each mouse. The gene expression profile of EF epidermis was most similar to that of anagen epidermis, consistent with activation of beta-catenin signalling. In contrast, adult dermis with ectopic hair follicles more closely resembled neonatal dermis than adult telogen or anagen dermis. In particular, genes associated with mitosis were upregulated and extracellular matrix-associated genes were downregulated in neonatal and EF fibroblasts. We confirmed that sustained epidermal beta-catenin activation stimulated fibroblasts to proliferate to reach the high cell density of neonatal skin. In addition, the extracellular matrix was comprehensively remodelled, with mature collagen being replaced by collagen subtypes normally present only in developing skin. The changes in proliferation and extracellular matrix composition originated from a specific subpopulation of fibroblasts located beneath the sebaceous gland. Our results show that adult dermis is an unexpectedly plastic tissue that can be reprogrammed to acquire the molecular, cellular and structural characteristics of neonatal dermis in response to cues from the overlying epidermis.
2011-10-13 | GSE32966 | GEO
Project description:ILK is essential for proper development of hair follicles, and for epidermal integrity and repair after injury. To better understand the pathways modulated by ILK in the epidermis, we compared the transcriptomes of ILK-deficient and -expressing epidermis using microarray analyses.
2012-01-18 | GSE35129 | GEO
Project description:ILK is essential for proper development of hair follicles, and for epidermal integrity and repair after injury. To better understand the pathways modulated by ILK in the epidermis, we compared the transcriptomes of ILK-deficient and -expressing epidermis using microarray analyses. Ilktm1Star (with floxed Ilk alleles) and Tg(KRT14-cre)1Amc/J mice were bred, and the resulting mice were bred again with Ilktm1Star mice, to generate animals heterozygos for the KRT14-cre transgene and either heterozygous (ILK-expressing) or homozygous (ILK-deficient) for the floxed Ilk alleles. The epidermis of 3 day-old animals was harvested and used to prepare RNA for the microarrays. The animals used were littermates. RNA from the epidermis of five ILK-deficient and five ILK-expressing mice were used.
2012-01-18 | E-GEOD-35129 | biostudies-arrayexpress
Project description:Integrin-linked kinase (ILK) links integrins to the actin cytoskeleton and is believed to phosphorylate several target proteins. We report that a keratinocyte-restricted deletion of the ILK gene leads to epidermal defects and hair loss. ILK-deficient epidermal keratinocytes exhibited a pronounced integrin-mediated adhesion defect leading to epidermal detachment and blister formation, disruption of the epidermal-dermal basement membrane, and the translocation of proliferating, integrin-expressing keratinocytes to suprabasal epidermal cell layers. The mutant hair follicles were capable of producing hair shaft and inner root sheath cells and contained stem cells and generated proliferating progenitor cells, which were impaired in their downward migration and hence accumulated in the outer root sheath and failed to replenish the hair matrix. In vitro studies with primary ILK-deficient keratinocytes attributed the migration defect to a reduced migration velocity and an impaired stabilization of the leading-edge lamellipodia, which compromised directional and persistent migration. We conclude that ILK plays important roles for epidermis and hair follicle morphogenesis by modulating integrin-mediated adhesion, actin reorganization, and plasma membrane dynamics in keratinocytes.
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Project description:Available evidence has suggested that integrin-linked kinase (ILK) underwent over-expression in ovarian cancer while specific gene silencing of ILK resulted in apoptosis of ovarian cancer cells. Here, potential mechanisms in which ILK induces cell apoptosis was explored from the perspective of microRNA (miRNA) expression. Alteration in global miRNA expression profile was detected by miRNA microarray technique after ILK shRNA expression lentivirus was transfected into A2780 cells (n = 3). Additionally, the A2780 cells infected by scrambled shRNA lentivirus were treated as negtive control (n = 3).
2016-06-28 | E-GEOD-83721 | biostudies-arrayexpress
Project description:Available evidence has suggested that integrin-linked kinase (ILK) underwent over-expression in ovarian cancer while specific gene silencing of ILK resulted in apoptosis of ovarian cancer cells. Here, potential mechanisms in which ILK induces cell apoptosis was explored from the perspective of microRNA (miRNA) expression.
2016-06-28 | GSE83721 | GEO
Project description:Epidermal keratinocytes were isolated from adult murine skin and FACS sorted into three populations based on their surface maker expression of alpha 6 integrin, CD34 and Sca-1. <br>- Alpha 6 positive cells constitute the entire population of basal or proliferative keratinocytes from the interfollicular epidermis and hair follicle. Both BIB and Bulge cells are contained within the total population of alpha 6 positive cells. <br>- BIB cells reside in the hair follicle in a region between the infundibulum and bulge and these cells are characterized by low alpha 6 integrin surface levels and are negative for CD34 and Sca-1 surface proteins. <br>- Bulge cells are derived from the bulge region of the hair follicle and are characterized by low + high alpha 6 integrin surface levels and are positive for CD34 but negative for Sca-1.
2009-11-16 | E-MEXP-928 | biostudies-arrayexpress