Regulation of the Hippo pathway by phosphoinositol transfer protein (PITP) and phosphoinositides
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ABSTRACT:
PROVIDER: PRJNA817255 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18360389_1.fastq.gz | Fastqsanger.gz | |||
| SRR18360389_2.fastq.gz | Fastqsanger.gz | |||
| SRR18360390_1.fastq.gz | Fastqsanger.gz | |||
| SRR18360390_2.fastq.gz | Fastqsanger.gz | |||
| SRR18360391_1.fastq.gz | Fastqsanger.gz |
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Project description:The Hippo pathway plays a key role in development, organ size control, and tissue homeostasis, and its dysregulation contributes to cancer. The LATS tumor suppressor kinases phosphorylate and inhibit the YAP/TAZ transcriptional co-activators to suppress gene expression and cell growth. Through a screen of marine natural products, we identified microcolin B (MCB) as a Hippo activator. Structure-activity optimization yielded more potent MCB analogs, which led to identification of PITP as the direct molecular targets. We established a critical role of PITP in regulating LATS and YAP. Moreover, we showed that PITP influences the Hippo pathway via cellular PI4P. This study uncovers a previously unrecognized role of PITP in Hippo pathway regulation and as potential cancer therapeutic targets.
2022-03-20 | GSE198890 | GEO
Project description:The Hippo pathway, which is conserved from Drosophila to mammals, has been recognized as a tumor suppressor signaling pathway governing cell proliferation and apoptosis, two key events involved in organ size control and tumorigenesis. Although several upstream regulators, the conserved kinase cascade and key downstream effectors including nuclear transcriptional factors have been defined, the global organization of this signaling pathway is not been fully understood. Thus, we conducted a proteomic analysis of human Hippo pathway, which revealed the involvement of an extensive protein-protein interaction network in this pathway. Our data suggest that 550 interactions within 343 unique protein components constitute the central protein-protein interaction landscape of human Hippo pathway. Our study provides a glimpse into the global organization of Hippo pathway, reveals previously unknown interactions within this pathway, and uncovers new potential components involved in the regulation of this pathway. Understanding these interactions will help us further dissect the Hippo signaling-pathway and extend our knowledge of organ size control. Mass spectrometry data anaylsis: Excised gel bands were cut into approximately 1 mm3 pieces. Gel pieces were then subjected to in-gel trypsin digestion and dried. Samples were reconstituted in 5 ul of HPLC solvent A (2.5% acetonitrile, 0.1% formic acid). A nano-scale reverse-phase HPLC capillary column was created by packing 5 um C18 spherical silica beads into a fused silica capillary (100 um inner diameter x 20 cm length) with a flame-drawn tip. After equilibrating the column each sample was loaded via a Famos autosampler (LC Packings, San Francisco CA) onto the column. A gradient was formed and peptides were eluted with increasing concentrations of solvent B (97.5% acetonitrile, 0.1% formic acid). As peptides eluted they were subjected to electrospray ionization and then entered into an LTQ Velos ion-trap mass spectrometer (ThermoFisher, San Jose, CA). Peptides were detected, isolated, and fragmented to produce a tandem mass spectrum of specific fragment ions for each peptide. Peptide sequences (and hence protein identity) were determined by matching protein databases with the acquired fragmentation pattern by the software program, SEQUEST (ver. 28). (ThermoFisher, San Jose, CA). Enzyme specificity was set to partially tryptic with 2 missed cleavages. Modifications included carboxyamidomethyl (cysteines, fixed) and oxidation (methionine, variable). Mass tolerance was set to 2.0 for precursor ions and 1.0 for fragment ions. The database searched was the Human IPI databases version 3.6. Because we used HEK293 cells the Human IPI database was used. The number of entries in the database was 160,900 which included both the target (forward) and the decoy (reversed) human sequences. Spectral matches were filtered to contain less than 1% FDR at the peptide level based on the target-decoy method. Finally, only tryptic matches were reported and spectral matches were manually examined. When peptides matched to multiple proteins, the peptide was assigned so that only the most logical protein was included (Occam's razor). This same principle was used for isoforms when present in the database.
2013-10-17 | PXD000415 | Pride
Project description:Regulation of hepatocyte proliferation and liver morphology is of critical importance to tissue and whole-body homeostasis. However, the molecular mechanisms that underlie this complex process are incompletely understood. Here we describe a novel role for the ubiquitin ligase BRAP in regulation of hepatocyte morphology and turnover via regulation of MST2, a protein kinase in the Hippo pathway. The Hippo pathway has been implicated in control of liver morphology, inflammation and fibrosis. We demonstrate here that liver-specific ablation of Brap in mice results in gross and cellular morphological alterations of the liver. Brap-deficient livers exhibit increased hepatocyte proliferation, cell death, and inflammation. We show that loss of BRAP protein alters Hippo pathway signaling, causing a reduction in phosphorylation of YAP and increased expression of YAP target genes, including those regulating cell growth and interactions with the extracellular environment. Finally, increased Hippo signaling in Brap knockout mice alters the pattern of liver lipid accumulation in dietary models of obesity. These studies identify a role for BRAP as a modulator of the hepatic Hippo pathway with relevance to human liver disease. tissue and whole-body homeostasis. However, the molecular mechanisms that underlie this complex process are incompletely understood. Here we describe a novel role for the ubiquitin ligase BRAP in regulation of hepatocyte morphology and turnover via regulation of MST2, a protein kinase in the Hippo pathway. The Hippo pathway has been implicated in control of liver morphology, inflammation and fibrosis. We demonstrate here that liver-specific ablation of Brap in mice results in gross and cellular morphological alterations of the liver. Brap-deficient livers exhibit increased hepatocyte proliferation, cell death, and inflammation. We show that loss of BRAP protein alters Hippo pathway signaling, causing a reduction in phosphorylation of YAP and increased expression of YAP target genes, including those regulating cell growth and interactions with the extracellular environment. Finally, increased Hippo signaling in Brap knockout mice alters the pattern of liver lipid accumulation in dietary models of obesity. These studies identify a role for BRAP as a modulator of the hepatic Hippo pathway with relevance to human liver disease.
2022-02-28 | GSE196012 | GEO
Project description:Gastric cancer is still one of the most common cancer types and third leading cause of cancer deaths worldwide. Recent studies have showed that the Hippo signaling pathway plays a critical role in progression of gastric cancer. It is of great importance to demonstrate the regulation of Hippo signaling pathway and the degradation of YAP protein in gastric cancer. In this study, we found that OTUB1 is a critical factor to facilitate gastric cancer cell stemness and progression, which deubiquitinated and stabilized YAP protein.
2022-02-24 | GSE197135 | GEO
Project description:The Hippo pathway is an emerging signaling cascade involved in the regulation of organ size control. It consists of evolutionally conserved protein kinases that are sequentially phosphorylated and activated. The active Hippo pathway subsequently phosphorylates a transcription coactivator, YAP, which precludes its nuclear localization and transcriptional activation. Identification of transcriptional targets of YAP in diverse cellular contexts is therefore critical to the understanding of the molecular mechanisms in which the Hippo pathway restricts tissue growth. We used microarrays to profile the gene expression patterns upon acute siRNA knockdown of Hippo pathway components in multiple mammalian cell lines and identified a set of genes representing immediate transcriptional targets of the Hippo/Yap signaling pathway. Three mammalian cell lines (HEK293T, HepG2, HaCaT) were transfected with scramble siRNA controls or siRNAs against NF2 and LATS2, two core components of the Hippo pathway, simultaneously. Total RNAs were harvested four days after transfection to reveal the gene expression pattern unsing microarry. YAP and TAZ siRNAs were also transfected along with NF2 and LATS2 siRNAs to identify YAP/TAZ-dependent transcriptional targets upon loss of NF2/LATS2.
2013-12-31 | E-GEOD-49384 | biostudies-arrayexpress
Project description:The hippo pathway effector protein YAP modulated resistance to trametinib neuroblastomas with hyperactivated RAS pathway signalling
| PRJNA540060 | ENA
Project description:We used RNA-seq to study the function of FABP5 in gastric cancer cells (AGS and MGC803). Down-regulation of FABP5 suppressed cell proliferation, cell migration and invasion, and induced cell apoptosis. Bioinformatics analysis revealed that Hippo signaling pathway was related to FABP5 in GC cells.Our data suggested that FABP5 might act as a potential target associated with Hippo signaling pathway for GC treatment.
2022-12-31 | GSE171838 | GEO
Project description:The Hippo pathway kinase LATS1 scaffolds Beclin1 in autophagy regulation in hepatocellular carcinoma
| PRJNA481070 | ENA
Project description:Bombesin receptor subtype-3 (BRS3) is an orphan G-protein coupled receptor (GPCR) that involved in a range of pathological and physiological processes, while its biological functions and underlying regulatory mechanisms remain largely unknown. Quantitative phosphoproteomics approach was employed in this study to comprehensively decipher the signal transductions that occurred upon intracellular BRS3 activation. Lung cancer cell line H1299-BRS3 was treated with MK-5046, an agonist of BRS3, for different durations. Harvested cellular proteins were digested and phosphopeptides were enriched by immobilized titanium (IV) ion affinity chromatography (Ti4+-IMAC) for label-free quantification analysis. In total, 12,052 phosphopeptides were identified, corresponding to 4,015 phosphoproteins and 10,820 phosphosites. Data analysis revealed that 27 phosphopeptides corresponding to 6 proteins were involved in Hippo signaling pathway, which was significantly regulated by the activation of BRS3. Verification experiments demonstrated down-regulation of Hippo signaling pathway could induce the dephosphorylation and nucleus localization of Yes-associated protein (YAP), which further confirmed its association with cell migration through kinase inhibition. Our data collectively demonstrate that BRS3 activation contributes to cell migration through down-regulating Hippo signaling pathway.
2023-07-12 | PXD035666 | Pride
Project description:The Hippo pathway functions as a tumor-suppressor pathway in human cancers, while the dys-function of Hippo pathway is frequently observed in malignancies. Although the YAP/TAZ activity is tightly controlled by the phosphorylation cascade of MST-LATS-YAP/TAZ axis, it is still unclear why YAP/TAZ protein is activated in human cancers, even Hippo pathway is still active. Besides phosphorylation, recent studies implicate that several post-translational modifications also play critical roles in modulating TAZ function, including ubiquitination. Here, by a DUB (Deubiquitinases) siRNA screening library, we discovered DUB1 as a critical modulator to facilitate gastric cancer stemness and progression, which deubiquitinated and activated TAZ protein. We also identified DUB1 was elevated in gastric cancer, which correlated with TAZ activation and poor survival. DUB1 associated with TAZ protein and deubiquitinated TAZ at several lysine sites, which subsequently stabilized and facilitated TAZ function. Our study revealed a novel deubiquitinase of Hippo/TAZ axis and one possible therapeutic target for Hippo-driven gastric cancer.
2022-02-12 | GSE196262 | GEO