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Integrin α5-SRC signaling induces TET1 mediated hydroxymethylation of genes critical for maintenance of hepatic polarity

ABSTRACT: Conclusions: 1. ITGα5-SRC signalling regulates the CLDN1 expression and hepatic polarity. 2. ITGα5-SRC signalling regulates the TET catelyzed DNA 5hmc/5mc level. 3. Itgα5 regulates hydroxymethylation level of genes critical for polarity in vivo. 4. Excessive deposition of ECM blocks the regulatory effect of ITGα5 on CLDN1 in vitro and in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE162409 | GEO | 2022/11/10

REPOSITORIES: GEO

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Integrin α5-SRC signaling induces TET1 mediated hydroxymethylation of genes critical for maintenance of hepatic polarity.

Project description:Conclusions:1、 ITGα5-SRC signalling regulates the CLDN1 expression and hepatic polarity.2、ITGα5-SRC signalling regulates the TET catelyzed DNA 5hmc/5mc level. 3、Itgα5 regulates hydroxymethylation level of genes critical for polarity in vivo. 4、Excessive deposition of ECM blocks the regulatory effect of ITGα5 on CLDN1 in vitro and in vivo.

2022-10-03 | GSE159053 | GEO

Integrin α5-SRC signaling induces TET1 mediated hydroxymethylation of genes critical for maintenance of hepatic polarity

Project description:Integrin α5-SRC signaling induces TET1 mediated hydroxymethylation of genes critical for maintenance of hepatic polarity

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Integrin α5-SRC signaling induces TET1 mediated hydroxymethylation of genes critical for maintenance of hepatic polarity.

Project description:Integrin α5-SRC signaling induces TET1 mediated hydroxymethylation of genes critical for maintenance of hepatic polarity.

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α5 integrin regulates hepatic tight junctions through SRC-TET1-mediated DNA hydroxymethylation.

Project description:The functional tight junctions' integrity plays an important role in liver physiology. A variety of liver diseases have been associated with the perturbation of tight junctions. Herein, we showed that the lower expression of α5 integrin in hepatocytes in patients with liver cirrhosis is associated with matrix deposition in the space of Disse. Selective silencing of α5 integrin in hepatocytes compromised the ultrastructure of tight junctions by downregulating claudin 1 in an SRC (proto-oncogene, non-receptor tyrosine kinase) signaling-dependent manner. α5 integrin signaling induced SRC-TET-mediated changes in 5-hydroxymethylcytosine and 5-methylcytosine levels in hepatocytes in vitro and in vivo. hMeDIP sequencing showed intergenic hypohydroxymethylation of the claudin 1 gene in hepatocytes after α5 integrin silencing in mice. Therefore, understanding the mechanisms regulating hepatic tight junction integrity in which α5 integrin-SRC signaling and epigenetic modifications cooperate might help advance the development of useful diagnostics and therapeutic approaches for liver disease.

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Ambra1 spatially regulates Src activity and Src/FAK-mediated cancer cell invasion via trafficking networks

Project description:Here, using mouse squamous cell carcinoma cells, we report a completely new function for the autophagy protein Ambra1 as the first described ‘spatial rheostat’ controlling the Src/FAK pathway. Ambra1 regulates the targeting of active phospho-Src away from focal adhesions into autophagic structures that cancer cells use to survive adhesion stress. Ambra1 binds to both FAK and Src in cancer cells. When FAK is present, Ambra1 is recruited to focal adhesions, promoting FAK-regulated cancer cell direction-sensing and invasion. However, when Ambra1 cannot bind to FAK, abnormally high levels of phospho-Src and phospho-FAK accumulate at focal adhesions, positively regulating adhesion and invasive migration. Spatial control of active Src requires the trafficking proteins Dynactin 1 and IFITM3, which we identified as Ambra1 binding partners by interaction proteomics. We conclude that Ambra1 is a core component of an intracellular trafficking network linked to tight spatial control of active Src and FAK levels, and so crucially regulates their cancer-associated biological outputs.

2017-04-04 | PXD006002 | Pride

Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation

Project description:Despite significant progress, our understanding of how specific oncogenes transform cells is still limited and likely underestimates the complexity of downstream signalling events. Herein, we describe a novel, integrated approach that addresses this knowledge gap. This utilizes mass spectrometry-based chemical proteomics to characterize the global impact of an oncogene on the expressed kinome, and then functionally annotates the regulated kinases. As an example, we identified approximately seventy protein kinases exhibiting altered expression and/or phosphorylation in Src-transformed mammary epithelial cells. An integrated siRNA screen identified nine kinases, including SGK1, as being essential for Src-induced transformation. In triple negative breast cancer cells, which exhibit a prominent signalling network governed by src family kinases, Src positively regulated SGK1 expression and combined inhibition of Src and SGK1 was more effective at inhibiting colony formation in vitro, and xenograft growth in vivo, than either treatment alone. Therefore, this approach not only provides major mechanistic insights into oncogenic transformation but also aids the design of improved therapeutic strategies.

2019-01-14 | PXD010687 | Pride

Individual SRC-2 and SRC-3 knock-down in MCF-7 cells

Project description:Experimental aim: identification of SRC-2 and SRC-3-related genes in MCF-7 breast cancer cells. Experimental workflow: 1. shRNA transduction. MCF-7 cells were transduced with a mix of lentiviral particles containing five individual lentiviral pLKO.1-puro short hairpin (sh) RNA plasmids targeting different sequences on SRC-2 or SRC-3 mRNA and a pLKO.1-puro empty vector control. The puromycin selections were maintained for three weeks to obtain cells containing stably integrated shRNA. 2. Sample preparation. RNA was extracted from eight independent replicates expressing the pLKO.1-puro empty shRNA vector (shKTR), from eight replicates of SRC-2 shRNA expressing cells (shSRC-2), and from seven replicates of SRC-3 shRNA expressing cells (shSRC-3). 300 ng of total RNA from each cell sample was biotin-labelled and amplified.

2019-07-01 | E-MTAB-7018 | biostudies-arrayexpress

The TGF-β/SMAD pathway upregulates SRC

Project description:The non-receptor tyrosine kinase SRC is upregulated in various human cancers and plays crucial roles in cancer progression by promoting invasion and metastasis. We show that the transforming growth factor beta (TGF-β/SMAD pathway directly upregulates SRC during the epithelial-mesenchymal transition. In human epithelial MCF10A cells, TGF-β1 treatment markedly upregulated mRNA expression of SRC. Knockout of SMAD4 suppressed upregulation of SRC by TGF-β1. ChIP-sequencing analysis revealed that SRC was transcribed from the SRC1A promoter, which interacted with SMAD2 and SMAD4, in response to TGF-β1. These findings demonstrate that a direct interaction of the activated SMAD complex with the SRC1A promoter directly upregulates SRC and suggest that TGF-β contributes to SRC upregulation in the tumor microenvironment, where TGF-β-mediated tumor progression takes place.

2023-11-20 | GSE122913 | GEO

Fat body-derived cytokine Upd2 regulates the polarity of Drosophila tracheal stem cells [RNA-seq]

Project description:Adult stem cells are essential for maintaining tissue homeostasis. We employ Drosophila tracheal progenitors to understand the mechanism controlling the polarity of stem cell migration. Here, we show that polarity of tracheal progenitors depends on the function of fat body. Cytokine, Upd2, produced by fat body, signals to tracheal progenitors and activation JAK/STAT signal transduction. Perturbation of Upd2 production or loss-of-function of JAK/STAT signaling in the trachea cause aberrant bidirectional migration of tracheal progenitors. JAK/STAT signaling promotes the expression of a series of genes involved in planar cell polarity, which generates asymmetric localization of Fat and Pod1. Furthermore, the transport of Upd2 requires Rab5-, Rab7-mediated endocytic sorting and Lbm-dependent vesicle trafficking, where vesicular Upd2 functionally interacts with Rabs, Tetraspanin and Grasp65. These results reveal an inter-organ communication in which cytokines from fat body direct the polarity of ectodermal origin tracheal progenitors and suggest that Upd2-dependent JAK/STAT signaling regulates anterior-posterior polarity of tracheal progenitor movement.

2024-10-28 | GSE256177 | GEO

Gene profiling analysis of Src chemical rescue

Project description:The restoration of catalytic activity to mutant enzymes by small molecules is well-established for in vitro systems. Here we show that the protein tyrosine kinase Src R388A mutant can be rescued in live cells using the small molecule imidazole. Cellular rescue of a v-Src homolog was rapid and reversible and conferred predicted oncogenic properties. Using chemical rescue in combination with mass spectrometry, six known Src kinase substrates were confirmed, and several new protein targets identified. Chemical rescue data suggests that c-Src is active under basal conditions. Rescue of R388A c-Src also allowed contributions of Src to the MAP kinase pathway to be clarified. This chemical rescue approach is likely to be of broad utility in cell signaling. We were also interested in examining the impact of Src rescue on the kinetics of gene expression. Chronic gene expression changes in v-Src transformed colon cancer and NIH3T3 cells have been reported, but the chemical rescue method permits insights into rapid kinetic changes. We used gene microarray analysis of imidazole activated Src, 1 h after imidazole treatment of 8A7F cells as well as 6N7F control cells, a set of several genes show increases (>1.7-fold) at 1 h in the 8A7F cells and another set show decreases (>1.7-fold) at 1 h with minimal changes in 6N7F control cells. Thirteen of these genes were further analyzed using real-time RT-PCR and most of the genes tested showed similar changes using both techniques. These gene changes were not reported in cells chronically transformed with v-Src or rapidly stimulated with growth factors suggesting that rapid initiation of Src-mediated tyrosine phosphorylation may induce a specialized pattern of gene expression changes. However, these earlier experiments were done under different conditions which may also contribute to gene effects. Keywords: time course, cell type comparison

2006-03-07 | GSE4043 | GEO

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