A non-canonical Hippo pathway represses the expression of deltaNp63
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ABSTRACT:
PROVIDER: PRJNA950997 | ENA |
REPOSITORIES: ENA
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Project description:Regulation of p63 expression occurs by a non-canonical version of the Hippo pathway in mammary epithelial, breast carcinoma and head and neck squamous carcinoma cells
2024-02-07 | GSE228680 | GEO
Project description:Müller glial cells (MGs) of the zebrafish retina exhibit the remarkable ability to reprogram to proliferative, retinal progenitor-like cells that can regenerate lost photoreceptors and restore vision. Unfortunately, mammalian MGs are not regenerative and this is at least in part due to the inability of MGs to undergo sustained cell cycle re-entry in response to retinal damage. Here, we identify the Hippo pathway as the core regulatory mechanism that normally prevents mammalian MG reprogramming to a proliferative, progenitor-like state. Specifically, in adult MGs within the damaged retina, Hippo signaling represses the activity of the transcription cofactor YAP, which would otherwise promote sustained MG cell cycle re-entry. MG-specific deletion of Hippo pathway components Lats1 and Lats2 resulted in Cyclin D1 upregulation and spontaneous MG proliferation. These data suggest that sustained YAP activity in reactive MGs induces MG proliferation and reprogramming, but this response is normally repressed by the Hippo pathway. Generation of MGs that express a variant of YAP (YAP5SA) that is non-responsive to Hippo signaling, resulted in cellular reprogramming whereby MG identity was lost and the cells acquired a highly proliferative, progenitor-like state. Together, our results reveal that MGs may have latent regenerative capacity that can be “reawakened” by blocking Hippo signaling.
2019-05-07 | GSE121707 | GEO
Project description:The sinoatrial node (SAN) functions as pacemaker of the heart to initiate and drive rhythmic heartbeats. The Hippo signaling pathway is a fundamental pathway for heart development and regeneration. Although abnormalities of Hippo pathway are associated with cardiac arrhythmias in human patients, yet its role in the SAN is unknown. We found that Lats1/2 inactivation caused severe sinoatrial node dysfunction (SND; sick sinus syndrome). Compared to the controls, Lats1/2 CKO mutants exhibited dysregulated calcium handling and increased fibrosis in the sinoatrial node, indicating Lats1/2 function through both cell-autonomous and non-cell-autonomous mechanisms. Notably, the Lats1/2 CKO phenotype was rescued by genetic deletion of Yap and Taz in the CCS, and these rescued mice had normal sinus rhythm and reduced fibrosis of the sinoatrial node, indicating that Lats1/2 function through Yap and Taz. CUT&Tag sequencing data showed that Yap regulates genes critical for calcium homeostasis such as Ryr2 and genes encoding paracrine factors important in intercellular communication and fibrosis induction such as Tgf-β1 and Tgf-β3. Consistently, Lats1/2 CKO mutants had decreased Ryr2 expression and increased Tgf-β1 and Tgf-β3 expression compared with control mice. We reveal for the first time that the canonical Hippo-Yap pathway has a pivotal role in functional homeostasis of the sinoatrial node.
2022-11-29 | GSE202641 | GEO
Project description:Hippo signaling pathway maintains sinoatrial node homeostasis
| PRJNA836869 | ENA
Project description:The canonical function of the Hippo signaling pathway is the regulation of organ growth. How this pathway controls cell fate determination is less well understood. Here, we identify a function of the Hippo pathway in cell fate decisions in the developing Drosophila eye, exerted through the interaction of Yorkie (Yki) with the transcriptional regulator Bonus (Bon), an ortholog of mammalian Transcriptional Intermediary Factor 1/tripartite motif (TIF1/TRIM) family proteins. Instead of controlling tissue growth, Yki and Bon promote epidermal and antennal fates at the expense of the eye fate. Proteomic, transcriptomic, and genetic analyses reveal that Yki and Bon control these cell fate decisions by recruiting transcriptional and post-transcriptional co-regulators, and by repressing Notch target genes and activating epidermal differentiation genes. Our work expands the range of functions and regulatory mechanisms under Hippo pathway control.
2023-01-17 | GSE181299 | 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:One challenge of cancer precision medicine is the heterogeneity of genetic and non-genetic alterations that result in dysfunctional molecular pathways. As an emerging drug discovery effort, dysregulation in Hippo pathway signaling is known to drive oncogenesis across numerous cancer types but lacks recurrent mutation(s) that are often found in other canonical signaling pathways. Here, we use first principles approach to develop a machine-learning framework to identify a robust, lineage-independent gene expression signature to quantify Hippo pathway dependency in cancers. Through integrating data from multi-omics platforms, this data-driven approach has enabled identifying a proposed combination with MAPK inhibition for direct targeting of Hippo pathway dependent cancers for which we then elucidate the underlying molecular mechanism. The results underscore how a multifaceted approach, computational models combined with laboratory efforts, can accelerate precision medicine efforts toward co-targeting Hippo and MAPK pathways, an approach that can be generalized to other key cancer signaling pathways to define therapeutic strategies.
2021-01-26 | GSE161018 | GEO
Project description:One challenge of cancer precision medicine is the heterogeneity of genetic and non-genetic alterations that result in dysfunctional molecular pathways. As an emerging drug discovery effort, dysregulation in Hippo pathway signaling is known to drive oncogenesis across numerous cancer types but lacks recurrent mutation(s) that are often found in other canonical signaling pathways. Here, we use first principles approach to develop a machine-learning framework to identify a robust, lineage-independent gene expression signature to quantify Hippo pathway dependency in cancers. Through integrating data from multi-omics platforms, this data-driven approach has enabled identifying a proposed combination with MAPK inhibition for direct targeting of Hippo pathway dependent cancers for which we then elucidate the underlying molecular mechanism. The results underscore how a multifaceted approach, computational models combined with laboratory efforts, can accelerate precision medicine efforts toward co-targeting Hippo and MAPK pathways, an approach that can be generalized to other key cancer signaling pathways to define therapeutic strategies.
2021-01-26 | GSE161010 | 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: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