Loss of the RING ligase praja2 boosts tyrosine kinase receptors in clear cell carcinoma
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ABSTRACT:
PROVIDER: PRJEB63462 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR11593014_1.fastq.gz | Fastqsanger.gz | |||
| ERR11593014_2.fastq.gz | Fastqsanger.gz | |||
| ERR11593015_1.fastq.gz | Fastqsanger.gz | |||
| ERR11593015_2.fastq.gz | Fastqsanger.gz | |||
| ERR11593016_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer in the adult population. Late diagnosis, resistance to therapeutics and recurrence of metastatic lesions account for the highest mortality rate among kidney cancer patients. Identifying novel biomarkers for early cancer detection and elucidating the mechanisms underlying ccRCC growth and progression will provide clues to treat this aggressive malignant tumor. Method: Expression studies of RING ligase praja2 and tyrosine kinase receptors (RTKs) in renal cell carcinoma was evaluated by immunoblot and immunohistochemistry. Gene transcription profiling in RCC cells was evaluated by RNA sequencing and Ingenuity Pathway Analysis. Imunofluorescence assays were used to evaluate the intracellular distribution and clearance of membrane receptors in cells devoid of praja2. Ubiquitin modifications and protein-protein interaction networks were monitored by IP, western blot, mass spectrometry and proteomic analysis. Experiments in vitro and in vivo were performed to define the role of praja2 in RTKs turnover, metabolism, renal cell carcinoma growth and metastatic diffusion. Results: We report here that the ubiquitin ligase praja2 controls endocytosis and the signal strength of different types of receptors (EGFR, VEGFR, TfR). Praja2 forms a complex with- and ubiquitinates the adaptor protein AP2m required for the activity of ATPase and acidification of endosomes and lysosomes necessary for receptor endocytosis and clearance. Downregulation of praja2 blocks the endocytosis of several membrane receptors, including EGFR, VEGFR and TfR and amplifies mitogenic and proliferative signaling as shown in the clear cell renal cell carcinoma (ccRCC). Restoring praja2 expression in RCC cells reduces EGFR levels, rewires cancer cell metabolism and inhibits growth and metastatic diffusion. In vivo, praja2 knockout mice show upregulation of tyrosine kinase receptors (RTKs) and pronounced histopathological renal alterations. Conclusion: Our findings identify praja2 as an important regulator of tyrosine kinase receptor(s) turnover and can be considered a bona fide oncosuppressor because it finely regulates signaling of several types of receptors and its loss supports kidney cancer growth and diffusion.
2024-02-01 | E-MTAB-13105 | biostudies-arrayexpress
Project description:Downregulation of RING ligase praja2 boosts receptor tyrosine kinases in kidney cancer
| PRJEB54648 | ENA
Project description:Clear cell renal cell carcinoma (ccRCC) is the most common variant of kidney cancer in the adult population. Late diagnosis, resistance to therapeutics and recurrence of metastatic lesions account for the highest mortality rate among kidney cancer patients. Identifying novel biomarkers for early cancer detection and the mechanisms underlying ccRCC growth and progression will provide clues to treat this aggressive malignant tumor. Here, we report that the RING ligase praja2 is a novel component of the endocytic system that supports clathrin-mediated receptor endocytosis. At molecular level, we identify the adaptor protein AP2 as a binding partner and substrate of praja2. Functionally, we demonstrate that praja2 is required for AP2-mediated receptor endocytosis and clearance. Downregulation of praja2 in RCC cells and tissues is associated with a marked upregulation of membrane receptors, as EGFR, VEGFR and TfR. A negative feedback loop links EGF signaling to proteolysis of praja2 and sustains downstream mitogenic and proliferative pathways. Restoring praja2 expression in RCC cells remarkably decreases EGFR levels, rewires cancer cell metabolism and inhibits RCC growth and metastatic diffusion. In praja2 knockout mice, upregulation of RTKs levels associates with profound histopathological renal alterations. Our findings identify praja2 as a component of the endocytic pathway that supports receptor endocytosis and clearance. Downregulation of praja2 in RCC cells, thus, sustains RTK signaling and promotes kidney cancer growth and diffusion.
2023-08-13 | E-MTAB-11900 | biostudies-arrayexpress
Project description:Clear cell renal cell carcinoma (ccRCC) is the most common variant of kidney cancer in the adult population. Late diagnosis, resistance to therapeutics and recurrence of metastatic lesions account for the highest mortality rate among kidney cancer patients. Identifying novel biomarkers for early cancer detection and the mechanisms underlying ccRCC growth and progression will provide clues to treat this aggressive malignant tumor. Here, we report that the RING ligase praja2 is a novel component of the endocytic system that supports clathrin-mediated receptor endocytosis. At the molecular level, we identify the adaptor protein AP2 as a binding partner and substrate of praja2. Functionally, we demonstrate that praja2 is required for AP2-mediated receptor endocytosis and clearance. Downregulation of praja2 in RCC cells and tissues is associated with a marked upregulation of membrane receptors, as EGFR, VEGFR and TfR. A negative feedback loop links EGF signaling to proteolysis of praja2 and sustains downstream mitogenic and proliferative pathways. Restoring praja2 expression in RCC cells remarkably decreases EGFR levels, rewires cancer cell metabolism and inhibits RCC growth and metastatic diffusion. In praja2 knockout mice, upregulation of RTKs levels associates with profound histopathological renal alterations. Our findings identify praja2 as a component of the endocytic pathway that supports receptor endocytosis and clearance. Downregulation of praja2 in RCC cells, thus, sustains RTK signaling and promotes kidney cancer growth and diffusion.
2024-05-21 | PXD034966 | Pride
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Project description:Robust cullin-RING ligase function is established by a multiplicity of poly-ubiquitylation pathways
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Project description:To identify substrates of the ubiquitinating E3 enzyme Rsp5 we applied purified Rsp5 to duplicate protein arrays. The Rsp proteins were expressed as fusion proteins to GST. We used as a control Ubr1, a RING domain containing E3 ligase We analyzed Rsp5 from S.cerevisiae on duplicate arrays, with four control chips, two without Rsp5 and two with Ubr1.
2008-12-30 | E-GEOD-14218 | biostudies-arrayexpress
Project description:To identify substrates of the ubiquitinating E3 enzyme Rsp5 we applied purified Rsp5 to duplicate protein arrays. The Rsp proteins were expressed as fusion proteins to GST. We used as a control Ubr1, a RING domain containing E3 ligase
2008-12-30 | GSE14218 | GEO
Project description:The large family of SCF ubiquitin ligases catalyze ubiquitylation by bridging protein substrates and ubiquitin-modifying enzymes. S. cerevisiae SCFs employ a sole, essential enzyme, Cdc34, to build poly-ubiquitin chains required for degradation. However, humans have no less than six chain building enzymes associated with SCFs, including the long assumed to be essential Cdc34 orthologs, UBE2R1 and UBE2R2. Furthermore, uncertainty regarding the physiological concentrations of ubiquitin-modifying enzymes has hindered in vitro mechanistic work. Proteomics was used to estimate enzyme levels in cells, and ubiquitylation assays were employed to quantitatively compare enzyme activities. The results show that UBE2R2 alone has negligible ubiquitylation activity at physiological concentrations, and the ablation of UBE2R1/2 had no effect on the stability of SCF substrates in cells. A genome-wide CRISPR screen revealed that UBE2G1 buffers against the deletion of UBE2R1/2. UBE2G1 had robust in vitro activity with SCF, and UBE2G1 knockdown in cells lacking UBE2R1/2 resulted in stabilization of the SCF substrate p27 as well as the Cul3-RING ligase substrate NRF2. The results reveal the human SCF enzyme system is heavily buffered and suggest that SCF specificity is diversified by association with multiple enzyme partners.
2020-01-01 | GSE136175 | GEO
Project description:JMJ24 is a RING motif containing Jumonji protein, whose E3 ligase activity is essential for communication between histone methylation and DNA methylation.In Arabidopsis JMJ24 is higly expressed in mature pollen. JMJ24 interacted with RDR2 and a single C4HC3 RING motif enabled JMJ24 to mono-ubiquitinate RDR2 for stabilization. RDR2 acted downsteam of JMJ24 for DNA methylation and local silencing. Here we performed tiling-array-based transcriptome profiling using mature pollen collected from WT and jmj24-1 and found that hundreds of loci encoding transposon elements, noncoding RNAs and protein-coding genes are regulated by JMJ24. WT vs. jmj24-1
2011-12-01 | E-GEOD-29708 | biostudies-arrayexpress