C-tail hyperphosphorylation activates PTEN oncogenic properties
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA849506 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19661836_1.fastq.gz | Fastqsanger.gz | |||
| SRR19661836_2.fastq.gz | Fastqsanger.gz | |||
| SRR19661837_1.fastq.gz | Fastqsanger.gz | |||
| SRR19661837_2.fastq.gz | Fastqsanger.gz | |||
| SRR19661838_1.fastq.gz | Fastqsanger.gz |
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Project description:PTEN is a multifaceted tumor suppressor that is highly sensitive to alterations in expression or function. The PTEN C-tail domain, which is rich in phosphorylation sites, has been implicated in PTEN stability, localization, catalytic activity, and protein interactions, but its role in tumor suppression remains unknown. To address this, we utilized several mouse strains with nonlethal C-tail mutations. Analysis of mice containing nonphosphorylatable or phosphomimetic versions of S380, a C-tail residue hyperphosphorylated in human gastric cancers, reveals that PTEN stability and ability to inhibit PI3K-AKT depends on dynamic phosphorylation-dephosphorylation of this residue. While phosphomimetic S380 drives neoplastic growth in prostate by promoting nuclear accumulation of β-catenin, nonphosphorylatable S380 is not tumorigenic. These data suggest that C-tail hyper-phosphorylation creates oncogenic PTEN and is a potential target for anti-cancer therapy.
2023-04-17 | GSE206157 | GEO
Project description:Ruxolinitib was approved by the FDA for the treatment of JAK2-V617F positive myelofibrosis. Unexpectedly, treatment of JAK2-V617F expressing cells with ruxolitinib causes paradoxical hyperphosphorylation of JAK2 at Tyr1007/1008 sites. The mechanism of ruxolitinib-induced JAK2 hyperphosphorylation is not well understood. A ruxolitinib-resistant JAK2 variant (V617F+L983F) and a JAK2-V617F kinase dead mutant (JAK2-V617F+K882R) did not show paradox hyperphosphorylation after ruxolitinib treatment indicating that ruxolitinib-mediated JAK2 hyperphosphorylation is mediated by a JAK2 intrinsic mechanism. Native immunocomplexes of JAK2-V617F with an antibody against pTyr1007/1008 could be blocked by the presence of ruxolitinib, although JAK2-V617F was hyperphosphorylated at these sites, suggesting that in the presence of ruxolitinib the JAK2 activation loop is buried within the kinase domain. This stabilization of the activation loop conformation results in the protection of pTyr1007/1008 sites from phosphatases. When JAK2 is in an inhibited conformationally restricted state, the phosphate group of Tyr1007 and Tyr1008 forms an intermolecular interaction with Arg975 and Lys999, respectively. Mutation of Arg975 and Lys999 to Ala reduced the phosphorylation at both Tyr1007/1008 residues, and importantly, ruxolitinib treatment did not lead to JAK2 hyperphosphorylation in these variants. Hyperphosphorylated JAK2 is hyperactive after ruxolitinib dissociation and activates STAT5 target genes PIM2, ID1, and MPL. Our results suggest a novel mode of kinase regulation by modulating kinase activity through conformational changes induced by ruxolitinib.
2025-02-01 | GSE284481 | GEO
Project description:RNAseq data from mouse MEFs with Pten C-tail phosphorylation sites mutation
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Project description:To investigate the effects of PTEN activity on gene expression in 3D cultured glioblastoma cells and the contributions of PTEN's lipid and protein phosphatase activities to these effects. We expressed wild type PTEN, a catalytically dead mutant (C124S) or mutants selectively lacking protein or lipid phosphatase activity (Y138L and G129E respectively) in U87MG cells at physiological levels by transient unselected polyclonal lentiviral transduction. Cells were then seeded into 3D matrigel and RNA prepared after 15 hours.
2012-02-28 | E-MTAB-989 | biostudies-arrayexpress
Project description:The PTEN:P-Rex2 complex is a commonly mutated signaling nodes in metastatic cancer. The dual-specificity phosphatase PTEN canonically functions as a tumour suppressor by hydrolysing PI(3,4,5)P3 to PI(4,5)P2 to inhibit PI3K-AKT signaling. P-Rex2 is a RhoGTPase guanine nucleotide exchange factor activated by both Gβγ and PI(3,4,5)P3 downstream of G protein-coupled receptor and receptor tyrosine kinase signaling. Assembly of the PTEN:P-Rex2 complex inhibits the activity of both proteins, and its dysregulation can drive PI3K-AKT signaling and cell proliferation. However, structural insights into both PTEN:P-Rex2 complex assembly and its dysregulation by cancer-associated mutations remain limited. Here, using crosslinking mass spectrometry and functional studies, we provide mechanistic insights into PTEN:P-Rex2 complex assembly and co-inhibition. PTEN is anchored to P-Rex2 by interactions between the PTEN C-terminal tail PDZ-interacting motif and the second PDZ domain of P-Rex2. This interaction bridges PTEN across the P-Rex2 surface, occluding PI(3,4,5)P3 hydrolysis. Conversely, PTEN both allosterically promotes an autoinhibited P-Rex2 conformation and occludes Gβγ binding. These insights allow us to define a new gain-of-function class of cancer mutations within the PTEN:P-Rex2 interface that uncouples PTEN inhibition of Rac1 signaling. In addition, we observe synergy between PTEN deactivating and P-Rex2 truncation mutations that combine to drive Rac1 activation to a greater extent than either single mutation alone.
2022-08-12 | PXD021126 | Pride
Project description:Decremental loss of PTEN results in cancer susceptibility and tumor progression. In turn this raises the possibility that PTEN elevation might be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with variably elevated PTEN expression levels, taking advantage of BAC (Bacterial Artificial Chromosome)-mediated transgenesis. Super-PTEN mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake, increased mitochondrial oxidative phosphorylation, and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and independent pathways, and negatively impacts two of the most pronounced metabolic features of tumor cells: glutaminolysis and the Warburg effect. In order to elucidate the pathophysiological impact of PTEN elevation, we generated transgenic mice carrying additional copies of this critical tumor suppressor gene (referred to as Super-PTEN mice). In order to maintain the regulation properties of the endogenous Pten gene, we made use of large genomic fragments containing the entire Pten locus carried by BACs (Bacterial Artificial Chromosomes). We next generated mouse embryonic fibroblasts (MEFs) and confirmed successful overexpression of PTEN by the BAC transgenic system. Primary cells derived from Super-PTEN mice represent a powerful tool to elucidate the molecular mechanisms underlying dose-dependent PTEN actions. We therefore performed microarray analysis in primary cells (MEFs) derived from day 13.5 embryos obtained by crossing Super-PTEN mice with C57BL6 mice. Three independent embryos from each genotype were analyzed (background: >98%C57BL6 / CBA). Gene expression profile analysis in these cells will reveal target genes and pathways differentially regulated upon PTEN elevation.
2012-12-01 | E-GEOD-35670 | biostudies-arrayexpress
Project description:WAP-Cre:Ptenf/f:p53lox.stop.lox_R270H composite mice were generated by genetic crossing. In these mice, Pten is deleted and a R270H p53 mutation in the DNA binding domain is induced upon expression of Cre recombinase in pregnancy-identified alveolar progenitors. Tumors were characterized by histology, marker analysis, various bioinformatics methods, high-throughput (HTP) FDA-drug screen as well as orthotopic injection to quantify tumor initiating cells (TICs) and tail-vein injection to identify lung-metastasis. Expression data comparing 2 types of Pten-deficient tumors (spindle and poorly differentiated) with other modles of mouse mammary tumors 2 types of Pten deletion plus p53-R270H mutation tumors (spindle and poorly differentiated) was compared with MMTV-Neu, Spindle Pten-p53-deficient tumors, and wild-type mammary gland cells.
2015-12-15 | E-GEOD-75989 | biostudies-arrayexpress
Project description:PTEN is one of the most frequently mutated tumor suppressor genes, its loss has been reported in multiple tumor types and is associated with a poor outcome. PTEN-L, as a secreted isoform of PTEN, with the ability to enter cells and inhibit tumor cell growth via inhibiting AKT mediated cell proliferation. However, the distinct effect of PTEN-L on PTEN-expression or PTEN-loss tumor cells is not known yet. Here, we identified PTEN-L treatment facilitate E0771-PTEN-null tumor cells, but not PTEN-wide-type tumor cells lung outgrowth. RNA-seq and Western blot analysis suggest PTEN-L stimulation induced PTEN-null tumor cells dormancy, namely, upregulation of dormancy markers p16 and p27, cell cycle arrest, reduced cell proliferation and chemotherapy drugs resistance. Further study suggested PTEN-L mediated p38 signaling activation play the major role for PTEN-null tumor cell dormancy. The p38 inhibitor, SB202190 significantly reversed the PTEN-L induced PTEN-null tumor cells dormancy and outgrowth in lungs. Further investigation indicated the dormant PTEN-null tumor cells could escape from immunosurveillance and thus outgrowth in lungs, as PTEN-L did not promote PTEN-null tumor cells outgrowth in lung of SCID mice. Therefore, we propose that PTEN-L protects PTEN-null tumor cells from immune attack during lung metastasis via activating dormancy related pathways. This study identified PTEN-L as an activator of PTEN-loss tumor cells dormancy, which enables the efficient seeding and outgrowth of tumor cells in metastatic niches. Overall, we highlight PTEN expression status decides the outcome of PTEN-L mediated anti-tumor therapy.
2024-05-17 | GSE246600 | GEO
Project description:Nuclear localization of PTEN is essential for its tumor suppressive role, and loss of nuclear PTEN is more prominent than cytoplasmic PTEN in many kinds of cancers. However, nuclear PTEN-specific regulatory mechanisms were rarely reported. Based on the finding that nuclear PTEN is more unstable than cytoplasmic PTEN. Thus, 293T cells were transiently transfected with plasmid encoding Flag-tagged PTEN along with empty vector, followed by affinity purification using an anti-Flag antibody, and the bound proteins were analyzed by liquid chromatography with tandem mass spectrometry (LC−MS/MS). Here we identify that F-box only protein 22 (FBXO22) induces ubiquitylation of nuclear but not cytoplasmic PTEN at lysine 221, which is responsible for the degradation of nuclear PTEN.
2020-04-22 | PXD017983 | Pride
Project description:PI3K/AKT/mTOR/PTEN signaling pathway is well known to regulate metabolism, cell growth and cell survival in all kinds of cells. PI3K phosphorylates PIP2(phosphoinositol-2 phosphate) into PIP3(phosphoinositol-3 phosphate) which acts as docking site for signaling components and activates Akt and mTOR signaling, whereas, Pten is a phosphatase which removes the phosphate from PIP3 and deactivates the singnaling. mTOR signaling encompasses two components namely mTORC1 and mTORC2 complexes and activity of these complexes orchestrated the various biological functions. Several studies have shown that loss of Pten in B cells disrupt the antibody class switching reaction and mTORC1 and mTORC2 has distinct role on the class switching reaction. However, the precise role of mTORC1 and mTORC2 conplexes in the Pten deficient condition is not yet studied. Notably, class switching reaction disrupted by loss of Pten, and that was restored only upon mTORC2 inactivation but not by mTORC1 inactivation in both of in vitro induced-germinal center B cells and plasmablasts culture condition.
2025-06-05 | GSE298707 | GEO