Effect of Gas6/Axl on HCC cell line gene expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE229731 | GEO | 2023/04/20
REPOSITORIES: GEO
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Project description:We investigated which signaling pathways downstream of Gas6/Axl promote the invasive phenotype of liver cancer cells. Thus, we performed phospho-proteomic analysis of MR hepatocytes and those expressing Axl (MR-Axl) in the presence and absence of Gas6. Protein-clustering based on the pattern of phosphorylation across the conditions and samples revealed four clusters: phospho-sites that are upregulated dependent on Axl expression (cluster 1) or Gas6 expression (cluster 2) and phospho-sites that are downregulated dependent on Axl expression (cluster 3) or Gas6 expression (cluster 4). Functional enrichment analysis showed enrichment of protein sets associated with cellular polarity and motility depending on changes in Axl expression and Gas6 activation. Furthermore, we analyzed phospho-proteomic data to estimate the activity of kinases based on kinase-substrate interactions using PhosR. Kinase perturbation analysis indicated mammalian target of rapamycin (mTOR) as the one with the highest upregulated activity in Gas6-stimulated MR-Axl cells compared to Gas6-stimulated MR cells. Accordingly, we analyzed substrates of mTOR and found that phosphorylation of Akt1 (Ser473) was upregulated in cluster 1 and highly increased in Gas6-stimulated MR-Axl, suggesting that Akt is regulated by Axl.
2024-05-23 | PXD047577 | Pride
Project description:Overexpression and amplification of AXL receptor tyrosine kinase (RTK) has been found in several hematologic and solid malignancies. Activation of AXL by its ligand GAS6 can enhance tumor-promoting processes such as proliferation, migration, invasion, and survival. Despite the important role of AXL in cancer development, a deep and quantitative mapping of its signaling transduction has not been performed. Here, we used a mass spectrometry-based quantitative proteomic approach to characterize the temporal dynamics of the phosphotyrosine proteome of MDA-MB-231 cells stimulated with GAS6
2021-08-24 | PXD025457 | Pride
Project description:Effect of Gas6/Axl on HCC cell line gene expression
| PRJNA955718 | ENA
Project description:Aggressive inflammation and excessive scar formation are the main cause to the difficulty of neural tissue repair after spinal cord injury (SCI). Microglia and astrocytes act as important role in this micro-environment of SCI and there is cross regulation between microglia and astrocytes. After SCI, MG0 polarized into MG1 and MG3 which were belong to pro-inflammatory phenotype microglia; Naive astrocytes polarized into Reactive and Scar-forming astrocytes. Growth arrest-specific 6 (Gas6) and its receptor Axl was declined in all these cells after SCI. In vitro study, Gas6 had the negative effect on cytotoxic astrocytes and pro-inflammatory microglia polarization and even the cross regulation between cytotoxic astrocytes and pro-inflammatory microglia. Further mechanism study indicated that Gas6 suppressed cytotoxic phenotype polarization of astrocytes through inhibited the activation of YES-associated protein (YAP) signal pathway and suppressed pro-inflammatory phenotype polarization of microglia through inhibited the activation of NF-κB/p65 and JAK/Stat3 signal pathways. In vivo study, Gas6 treatment suppressed cytotoxic astrocytes and pro-inflammatory microglia polarization at the injured site of spinal cord to facilitate tissue repair and loco-motor recovery.
2023-10-21 | GSE245470 | GEO
Project description:AXL is activated by its ligand GAS6 and is expressed in triple-negative breast cancer cells. We report that AXL is also detected in HER2+ breast cancer specimens where its expression correlates with poor patients’ survival. Using murine models of HER2+ breast cancer, AXL, but not Gas6, was found essential for metastasis. We determined that AXL is required for intravasation, extravasation and growth at the metastatic site. AXL is expressed in HER2+ cancers displaying EMT signatures and contributes to sustain EMT in murine tumors. Interfering with AXL in patient-derived xenograft impaired TGF-β-induced cell invasion. Lastly, pharmacological inhibition of AXL decreased the metastatic burden of mice developing HER2+ breast cancer. Our data identify AXL as a potential co-therapeutic target during the treatment of HER2+ breast cancers to limit metastasis.
2018-05-01 | GSE102368 | GEO
Project description:AXL is activated by its ligand GAS6 and is expressed in triple-negative breast cancer cells. We report that AXL is also detected in HER2+ breast cancer specimens where its expression correlates with poor patients’ survival. Using murine models of HER2+ breast cancer, AXL, but not Gas6, was found essential for metastasis. We determined that AXL is required for intravasation, extravasation and growth at the metastatic site. AXL is expressed in HER2+ cancers displaying EMT signatures and contributes to sustain EMT in murine tumors. Interfering with AXL in patient-derived xenograft impaired TGF-β-induced cell invasion. Lastly, pharmacological inhibition of AXL decreased the metastatic burden of mice developing HER2+ breast cancer. Our data identify AXL as a potential co-therapeutic target during the treatment of HER2+ breast cancers to limit metastasis.
2018-05-01 | GSE102369 | GEO
Project description:AXL is a receptor tyrosine kinase (RTK) which, together with TYRO3 and MER, belongs to the TAM receptor family. A ligand for AXL is growth arrest specific 6 (GAS6), which is able to bind all three TAMs with the highest affinity for AXL. AXL is overexpressed in a variety of different cancers, which correlates with poor prognosis, metastasis and drug resistance. However, its biology is still not fully understood and data concerning proteins that interact with this receptor are almost completely lacking. To identify mechanisms underlying the role of GAS6-AXL signaling in cancer, we established an AXL interactome using proximity-dependent biotin identification (BioID) assay. Experiments were conducted in HEK293 cells and human glioblastoma LN229 cells, which do not express and express AXL, respectively. The Gene Ontology (GO) analysis of biological processes indicated enrichment of proteins implicated in cell junction organization, axonogenesis, supramolecular fiber organization, angiogenesis and actin-related processes in bot, non-stimulated and GAS6-stimulated samples. Importantly, in samples with activated AXL, proteins implicated in actin-related processes were overrepresented. Consistent with this, we found that GAS6 stimulation triggered actin remodeling manifested by intense membrane ruffling and macropinocytosis. Our study provides comprehensive data about proteins interacting with AXL. Thus, the obtained results will help to understand the biology of the AXL receptor, particularly with respect to its involvement in cancer invasion.
2021-06-28 | PXD017933 | Pride
Project description:We sought to determine the effects of Gas6 on Alzheimer’s disease pathology through overexpression of Gas6 using an adeno-associated viral vector in the APP/PS1 model of Alzheimer’s disease. 9 month old male and female APP/PS1 and nontransgenic littermates received bilateral stereotactic hippocampal injections of AAV-Gas6 or AAV-control, an attenuated Gas6 protein that does not bind the Axl receptor. One month after injections, mice performed a battery of behavioral tasks and brains were processed for immunohistochemistry, transcriptional analyses, and flow cytometry.
2022-03-30 | GSE171195 | GEO
Project description:Anti-cancer therapies have been limited by emergence of mutations and other adaptations. In bacteria, antibiotics activate the SOS response, which mobilizes error‐prone factors that allow for continuous replication at the cost of mutagenesis. We investigated whether treatment of lung cancer with EGFR inhibitors (EGFRi) similarly engages hypermutators. In cycling drug-tolerant persister (DTP) cells and in EGFRi-treated patients presenting residual disease we observed upregulation of GAS6, while ablation of GAS6’s receptor, AXL, eradicated resistance. Reciprocally, AXL overexpression enhanced DTP survival and accelerated the emergence of T790M, an EGFR mutation typical to resistant cells. Mechanistically, AXL induces low-fidelity DNA polymerases and activates their organizer, RAD18, by promoting neddylation. Metabolomics uncovered another hypermutator, AXL-driven activation of MYC and increased purine synthesis that is unbalanced by pyrimidines. Aligning anti-AXL combination treatments with the transition from DTPs to resistant cells cured patient-derived xenografts. Hence, similar to bacteria, tumors tolerate therapy by engaging pharmacologically targetable endogenous mutators.
2022-11-17 | GSE202342 | GEO
Project description:Aortic remodeling is a cause and consequence of hypertension. It increases workload on the heart and enhances arterial pulsatility in the microcirculation. We have shown that excessive endothelial stretch leads to release of Growth Arrest Specific 6 (GAS6), which in turn activates the tyrosine kinase receptor Axl on monocytes, and causes immune activation and inflammation. We hypothesized that GAS6/Axl blockade would reduce renal and vascular inflammation and lessen renal dysfunction in the setting of chronic aortic remodeling. We characterized a model aortic remodeling in mice following a 2-week infusion of angiotensin II (ang II). Aortas demonstrated increased mural collagen and mechanical testing revealed a marked loss of Windkessel function or energy storage that persisted for 6 months following ang II. Renal function studies showed a reduced ability to excrete a volume load, a progressive increase in albuminuria and tubular damage as estimated by Periodic Acid Schiff (PAS) staining. Treatment with the Axl inhibitor R428 beginning 2 months after ang II infusion had minimal effect on aortic remodeling 2 months later, but reduced the infiltration of T cells, g/d T cells and macrophages into the aorta and kidney, and improved renal excretory capacity, reduced albuminuria, and reduced evidence of renal tubular damage. We conclude that brief episodes of hypertension can induce chronic aortic remodeling which in turn associates with a low-grade inflammation of the aorta and kidneys and evidence of renal dysfunction. These events are mediated at least in part by GAS6/Axl signaling and are improved with Axl blockade.
2022-12-31 | GSE205267 | GEO