MET∆14 promotes a ligand-dependent, AKT-driven invasive growth
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA800402 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17736724_1.fastq.gz | Fastqsanger.gz | |||
| SRR17736724_2.fastq.gz | Fastqsanger.gz | |||
| SRR17736725_1.fastq.gz | Fastqsanger.gz | |||
| SRR17736725_2.fastq.gz | Fastqsanger.gz | |||
| SRR17736726_1.fastq.gz | Fastqsanger.gz |
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Project description:MET is an oncogene encoding the tyrosine kinase receptor for hepatocyte growth factor (HGF). Upon ligand binding, MET activates multiple signal transducers, including PI3K/AKT (survival/migration), STAT3 (differentiation), and MAPK (proliferation). When mutated or amplified, MET becomes a "driver" for the onset and progression of cancer. The most frequent mutations in the MET gene affect the splicing sites of exon 14, leading to its "skipping" from mRNA and consequent deletion of the receptor's juxtamembrane domain (MET∆14). It is currently believed that, as in gene amplification, MET∆14 kinase is constitutively active. Analysis of MET in carcinoma cell lines showed that MET∆14 strictly depends on HGF for kinase activation. Compared to WT MET, ∆14 is sensitive to lower HGF concentrations, with more sustained kinase response, ultimately leading to a robust phosphorylation of AKT, without affecting MAPK or STAT3. This altered kinase response leads to a distinctive transcriptomic signature. Functional studies revealed that ∆14 activation is predominantly responsible for enhanced protection from apoptosis and cellular migration. Thus, the unique HGF-dependent ∆14 oncogenic activity suggests consideration of HGF in the tumour microenvironment to select patients for clinical trials.
2022-05-27 | GSE194382 | GEO
Project description:MET is an oncogene encoding the tyrosine kinase receptor for hepatocyte growth factor (HGF). Upon ligand binding, MET activates multiple signal transducers, including PI3K/AKT, STAT3, and MAPK. When mutated or amplified, MET becomes a "driver" for the onset and progression of cancer. The most frequent mutations in the MET gene affect the splicing sites of exon 14, leading to the deletion of the receptor's juxtamembrane domain (MET∆14). It is currently believed that, as in gene amplification, MET∆14 kinase is constitutively active. Our analysis of MET in carcinoma cell lines showed that MET∆14 strictly depends on HGF for kinase activation. Compared with wt MET, ∆14 is sensitive to lower HGF concentrations, with more sustained kinase response. Using three different models, we have demonstrated that MET∆14 activation leads to robust phosphorylation of AKT, leading to a distinctive transcriptomic signature. Functional studies revealed that ∆14 activation is predominantly responsible for enhanced protection from apoptosis and cellular migration. Thus, the unique HGF-dependent ∆14 oncogenic activity suggests consideration of HGF in the tumour microenvironment to select patients for clinical trials.
| S-EPMC9152130 | biostudies-literature
Project description:Amplification and activation of the Met receptor tyrosine kinase occurs up to 23% of gastric cancers, suggesting that Met is a therapeutic target in these cancers. However, the steady-state signaling events that occur during chronic Met activation, and mechanisms for resistance to Met small-molecule inhibitors, are poorly understood. Here we show that multiple gastric cancer cell lines harboring MET amplifications are dependent on Met signaling for proliferation and anchorage-independent growth. In these cells, short-term inhibition of Met leads to coordinated changes in gene expression; these include a rapid loss in expression of immediate-early genes, followed by decreased expression of genes involved in cell cycle and proliferation. Activation of Ras-Erk, PI3K-Akt and STAT3 pathways is attenuated by acute Met inhibition. STAT3 inhibition alone, but not individual inhibition of Mek or Akt, is sufficient to abrogate Met-dependent growth of these cells. However, following chronic Met inhibition, reactivation of Mek-dependent Erk phosphorylation occurs even in the presence of Met inhibitor corresponding with a downregulation of Erk negative regulators DUSP4/6. This provides a mechanism for the emergence of drug resistance. Our findings provide insights into innate resistance to a small-molecule Met inhibitor and highlight rational combination therapies that could be evaluated in clinical trials. Time series experiment, four cell lines, 2 treatments
2014-05-19 | E-GEOD-54532 | biostudies-arrayexpress
Project description:Amplification and activation of the Met receptor tyrosine kinase occurs up to 23% of gastric cancers, suggesting that Met is a therapeutic target in these cancers. However, the steady-state signaling events that occur during chronic Met activation, and mechanisms for resistance to Met small-molecule inhibitors, are poorly understood. Here we show that multiple gastric cancer cell lines harboring MET amplifications are dependent on Met signaling for proliferation and anchorage-independent growth. In these cells, short-term inhibition of Met leads to coordinated changes in gene expression; these include a rapid loss in expression of immediate-early genes, followed by decreased expression of genes involved in cell cycle and proliferation. Activation of Ras-Erk, PI3K-Akt and STAT3 pathways is attenuated by acute Met inhibition. STAT3 inhibition alone, but not individual inhibition of Mek or Akt, is sufficient to abrogate Met-dependent growth of these cells. However, following chronic Met inhibition, reactivation of Mek-dependent Erk phosphorylation occurs even in the presence of Met inhibitor corresponding with a downregulation of Erk negative regulators DUSP4/6. This provides a mechanism for the emergence of drug resistance. Our findings provide insights into innate resistance to a small-molecule Met inhibitor and highlight rational combination therapies that could be evaluated in clinical trials.
2014-05-19 | GSE54532 | GEO
Project description:MET exon 14 skipping alteration (MET∆14Ex) is an actionable oncogenic driver that occurs in 2-4% of non-small cell lung cancer (NSCLC) cases. However, the precise role of MET∆14Ex in tumor progression in NSCLC is poorly understood. We here demonstrate that MET∆14Ex expression increases receptor kinase activity and downstream signaling by impairing receptor internalization and endocytic degradation, which significantly boosts tumor cell scattering and invasion as well as metastasis. To explore the key mechanisms in regulation of these phenotypes, RNA sequencing (RNA-seq) studies were conducted on HGF-treated MET∆14Ex and MET cell models in an effort to identify the global change of transcriptome signature and key functional pathways involved in MET∆14Ex-medieated tumorigenesis. Both Ingenuity pathway analysis (IPA) and gene set enrichment analysis (GSEA) revealed an induction of a tight cluster of functional pathways associated with cell movement in HGF-treated MET∆14Ex models (vs MET) in a time-dependent manner.
2021-12-31 | GSE182684 | GEO
Project description:c-Met induces tumor initiation and stemness in HCC cells through the regulation of CD44s via AKT signaling. Over-expression of CD44s in c-Met and CD44s negative cells induce both a stemness and mesenchymal phenotype independent of c-Met. The down regulation of CD44s or c-Met was compared to Scrambled control to investigate the effects of CD44s or c-Met on global changes of mesenchymal or stemness markers.
2012-05-30 | E-GEOD-38343 | biostudies-arrayexpress
Project description:c-Met induces tumor initiation and stemness in HCC cells through the regulation of CD44s via AKT signaling. Over-expression of CD44s in c-Met and CD44s negative cells induce both a stemness and mesenchymal phenotype independent of c-Met.
2012-05-31 | GSE38343 | GEO
Project description:Effect of MET exon 14 skipping on gene expression stimulated or not by its ligand Hepatocyte Growth Factor (HGF) in pulmonary epithelial 16HBE cell line which undergone genome-editing by CRISPR-Cas9 technology.
2023-11-16 | GSE184514 | GEO
Project description:Despite the well-known role of MET in liver regeneration following partial-hepatectomy (PHx), its role in the clinically-relevant acetaminophen (APAP)-induced liver injury (AILI) model remains unexplored. AILI markedly differs from PHx because it is associated with massive liver necrosis. This study aims to delineate the role of MET specifically in AILI. Hepatocyte-specific MET-KO mice were given a toxic-dose of APAP and assessed for hepatotoxicity/regeneration parameters. MET deletion strikingly exacerbated initial hepatotoxicity and impaired subsequent proliferative response, culminating in significant mortality. Mechanistically, MET deletion enhanced JNK-activation and its mitochondrial translocation, resulting in excessive mitochondrial oxidative-damage, releasing cell-death inducer AIF into cytosol. Excess JNK-activation was attributed to reduced inhibitory activity of AKT on JNK in the absence of MET-signaling. Pharmacological activation of AKT reduced JNK-activation and hepatotoxicity in MET-KO mice. RNA-sequencing/immunoblotting not only showed repression of proliferative/survival signaling, but also activation of cell death/senescence pathways along with impaired unfolded-protein-response in MET-KO mice. Analysis of published single-nucleus RNA-sequencing data showed proliferation in livers from APAP-induced ALF patients was associated with strong activation of HGF/MET signaling in hepatocytes, with spatial-transcriptomics showing striking induction of HGF surrounding the necrotic-zones. Interestingly, 35% of the genes altered in human-ALF were regulated by MET in the mouse AILI-model. In conclusion, our study demonstrates that MET is crucial for restraining hepatotoxicity following APAP overdose via inhibiting mitochondrial cell-death signaling pathway.
2025-09-10 | GSE305543 | GEO
Project description:JH modulates phosphorylation modification of components of its intracellular signaling through putative membrane pathway. As a transcriptional factor, Met phosphorylation is contributed to its transcriptional activity, but whether phosphorylation modification affects Met nuclear import is unknown. Here, we report that phosphorylation sites are dispensable for NLS activity whether JH is present or not. Interestingly, binding affinity of Met and Hsp83 fails to increase by adding JH is resulted from the mutant of JH-regulated phosphorylation of Hsp83 at S219. JH also increase binding affinity of Hsp83 and 14-3-3 proteins independent on S219. 14-3-3 proteins negatively regulated JH activity through sequestrating Met in the cytoplasm that dependent on Hsp83, which acts as a bridge between Met/Gce and 14-3-3 proteins. These results suggest that JH membrane pathway phosphorylates either Met or Hsp83 to promote JH intracellular signaling, meanwhile, a negative feedback loop forms between the 14-3-3 proteins and Hsp83.
2021-07-15 | PXD027314 |