Impaired protein tyrosine phosphatase delta is a driver of hepatic metabolic syndrome
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA633851 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11811983.fastq.gz | Fastqsanger.gz | |||
| SRR11811984.fastq.gz | Fastqsanger.gz | |||
| SRR11811985.fastq.gz | Fastqsanger.gz | |||
| SRR11811986.fastq.gz | Fastqsanger.gz | |||
| SRR11811987.fastq.gz | Fastqsanger.gz |
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Project description:Background & Aims: The protein tyrosine phosphatase delta (PTPRD) is suppressed in several diseases including cancers and hepatitis C virus (HCV) infection. To identify hepatic pathways responsive to PTPRD function and their role in liver disease, we analyzed liver transcriptomic and clinical data from patients and established a Ptprd-deficient liver disease mouse model. Methods: Based on liver transcriptomic data, healthy patients were classified according to PTPRD expression and gene set enrichment analysis (GSEA) was performed to identify signaling pathways associated with low PTPRD expression. We established a liver disease mouse model combining impaired PTPRD expression (Ptprd+/-) and high-fat diet to assess its impact on liver transcriptomics and hepatic metabolism. Identified pathways were validated by perturbation studies in primary human hepatocytes. The clinical relevance was validated in a cohort of patients with fatty liver disease by ranking of individuals according to hepatic PTPRD expression prior analyzing the association with metabolic disease markers. Results: In healthy individuals and Ptprd+/- mice fed with normal diet, low PTPRD levels associated with a gene expression pattern involved in glucose/lipid metabolism in the liver. During diet-induced liver disease, low hepatic PTPRD led to increased blood glucose and hepatic lipid levels in the Ptprd+/- animals. Moreover, Ptprd+/- animals exhibited a pronounced unfolded protein response, which has a potential impact on hepatic insulin signaling. Indeed, silencing of PTPRD in PHH blunted the insulin-induced AKT phosphorylation. Accordingly, obese patients with low hepatic PTPRD expression exhibit increased levels of clinical markers associated with metabolic disease. Conclusion: Our data suggests an important regulatory role of hepatic PTPRD in maintaining glucose/lipid homeostasis and how its impaired expression is associated with clinical manifestations of metabolic disease.
2025-03-26 | GSE150848 | GEO
Project description:Background & Aims: Protein tyrosine phosphatase delta (PTPRD) is suppressed in several diseases including HCV infection. To identify hepatic pathways responsive to PTPRD function and their role in non-viral liver disease, we analyzed liver transcriptomic and clinical data from patients and established a Ptprd-deficient liver disease mouse model. Methods: Healthy patients were classified according to hepatic PTPRD expression and transcriptomic analysis was performed to identify signaling pathways associated with low PTPRD levels. We combined an animal model for metabolic dysfunction-associated steatohepatitis (MASH) with genetically impaired PTPRD expression (Ptprd+/-) to assess its impact on the liver transcriptome and metabolic function. Identified pathways were validated by perturbation studies in primary human hepatocytes and differentiated HepaRG cells. Substrate specificity was validated by pull-down assay. The clinical relevance was explored in a cohort of patients with fatty liver disease by ranking individuals according to hepatic PTPRD expression and analyzing its association with metabolic disease markers. Results: In healthy individuals and Ptprd+/- mice, PTPRD levels associated with hepatic glucose/lipid metabolism and peroxisomal function. Hepatic PTPRD expression is impaired in metabolic liver disease. Moreover, we revealed PTPRD as a STAT3 phosphatase in the liver, which is a regulator of peroxisomal function. Silencing of STAT3 in HepaRG cells treated with free-fatty acids was able to rescue the expression of genes implicated in lipid metabolism. During MASH, low hepatic PTPRD led to increased liver steatosis in the Ptprd+/- animals and pronounced unfolded protein response, which impacts insulin signaling. Silencing of PTPRD in PHH blunted insulin-induced AKT phosphorylation. In line with this, obese patients with low hepatic PTPRD expression exhibit increased levels of clinical markers associated with metabolic disease. Conclusion: Our data suggest an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis and how its impaired expression is associated with clinical manifestations of metabolic liver disease.
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Project description:Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease (HepaRG cells).
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Project description:Glioblastoma ranks among the most lethal of primary brain malignancies, with glioblastoma stem cells (GSCs) at the apex of tumor cellular hierarchies. Here, to discover novel therapeutic GSC targets, we interrogated gene expression profiles from GSCs, differentiated glioblastoma cells (DGCs), and neural stem cells (NSCs), revealing EYA2 as preferentially expressed by GSCs. Targeting EYA2 impaired GSC maintenance and induced cell cycle arrest, apoptosis, and loss of self-renewal. EYA2 displayed novel localization to centrosomes in GSCs, and EYA2 tyrosine (Tyr) phosphatase activity was essential for proper mitotic spindle assembly and survival of GSCs. Inhibition of the EYA2 Tyr phosphatase activity, via genetic or pharmacological means, mimicked EYA2 loss in GSCs in vitro and extended the survival of tumor-bearing mice. Supporting the clinical relevance of these findings, EYA2 portends poor patient prognosis in glioblastoma. Collectively, our data indicate that EYA2 phosphatase function plays selective critical roles in the growth and survival of GSCs, potentially offering a high therapeutic index for EYA2 inhibitors.
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Project description:Efforts to improve the clinical outcome of highly aggressive triplenegative breast cancer (TNBC) have been hindered by the lack of effective targeted therapies. Hence, it is important to identify the specific gene targets/pathways driving the invasive phenotype to develop more effective therapeutics. Here we show that UBASH3B (ubiquitin associated and SH3 domain containing B), a protein tyrosine phosphatase, is overexpressed in TNBC, where it supports malignant growth, invasion and metastasis in large through modulating EGFR. We also show that UBASH3B is a functional target of anti-invasive miR-200a that is downregulated in TNBC. Importantly, the oncogenic potential of UBASH3B is dependent on its tyrosine phosphatase activity, which targets CBL ubiquitin ligase for dephosphorylation and inactivation, leading to EGFR upregulation. Thus, UBASH3B may function as a crucial node in bridging multiple invasion-promoting pathways, thus providing a potential new therapeutic target for TNBC. Breast cancer tissues and breast cancer cell lines
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Project description:The delicate balance of protein phosphorylation is often disrupted in cancers, with hyperactivity of kinases and inactivation of phosphatases driving cell proliferation and survival pathways. PTPRH, a receptor-like protein tyrosine, is deregulated or mutated in certain cancers, including non-small cell lung cancer (NSCLC). Nonetheless, the biological processes that PTPRH is involved in and how it may contribute to tumorigenesis are unknown. We aimed to understand how ovexpression of PTPRH affects tyrosine kinase signaling and in which biological processess this tyrosine phosphatase is involved in. We observed that overexpression of the phosphatase downregulates multiple oncogenic signature pathways and modulates the gene expression of 34 protein tyrosine phosphatases and 45 tyrosine kinases, EGFR included. Moreover, we report for the first time that PTPRH is primarily involved in translation and RNA-associated pathways. Together, these results shed light on the importance of PTPRH in regulating biological and cellular processes and how its inactivation may support cancer progression.
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Project description:Efforts to improve the clinical outcome of highly aggressive triple-negative breast cancer (TNBC) have been hindered by the lack of effective targeted therapies. Thus, it is important to identify the specific gene targets/pathways driving the invasive phenotype to develop more effective therapeutics. Here we show that ubiquitin-associated and SH3 domain-containing B (UBASH3B), a protein tyrosine phosphatase, is overexpressed in TNBC, where it supports malignant growth, invasion, and metastasis largely through modulating epidermal growth factor receptor (EGFR). We also show that UBASH3B is a functional target of anti-invasive microRNA200a (miR200a) that is down-regulated in TNBC. Importantly, the oncogenic potential of UBASH3B is dependent on its tyrosine phosphatase activity, which targets CBL ubiquitin ligase for dephosphorylation and inactivation, leading to EGFR up-regulation. Thus, UBASH3B may function as a crucial node in bridging multiple invasion-promoting pathways, thereby providing a potential therapeutic target for TNBC.
2013-06-01 | GSE36693 | GEO
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