Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA317718 | ENA |
REPOSITORIES: ENA
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Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage derived sarcomas with poor prognosis. The molecular events underlying SC lineage cells-to-MPNST transformation remain elusive. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyper-proliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide target profiling reveals that TAZ/YAP-TEAD1 directly activates a set of oncogenic programs in SCs including PDGFR/RAF signaling. Co-targeting TAZ/YAP and PDGFR/RAF signaling efficaciously reduces tumorigenicity in Lats1/2-deficient tumors. Thus, our findings establish a previously unrecognized convergence between LATS1/2-TAZ/YAP pathway and MPNST pathogenesis, suggesting that combined inhibition of TAZ/YAP-PDGFR/RAF signaling may be beneficial in MPNSTs.
2018-02-13 | GSE99040 | GEO
Project description:YAP is an oncogene and an inducer of Epithelial-to-Mesenchymal Transition (EMT). We used microarrays to detail the global program of gene expression to identify YAP target genes. PUBLICATION ABSTRACT:; The Hippo pathway defines a novel signaling cascade regulating cell proliferation and survival in Drosophila, which involves the negative regulation of the transcriptional coactivator Yorkie by the kinases Hippo and Warts. We have recently shown that the human ortholog of Yorkie, YAP, maps to a minimal amplification locus in mouse and human cancers, and that it mediates dramatic transforming activity in MCF10A primary mammary epithelial cells. Here we show that LATS proteins (mammalian orthologs of Warts) interact directly with YAP in mammalian cells and that ectopic expression of LATS1, but not LATS2, effectively suppresses the YAP phenotypes. Furthermore, shRNA-mediated knockdown of LATS1 phenocopies YAP overexpression. Since this effect can be suppressed by simultaneous YAP knockdown, it suggests that YAP is the primary target of LATS1 in mammalian cells. Expression profiling of genes induced by ectopic expression of YAP or by knockdown of LATS1 reveals a subset of potential Hippo pathway targets implicated in epithelial-to-mesenchymal transition (EMT), suggesting that this is a key feature of YAP signaling in mammalian cells. Experiment Overall Design: MCF10A cells were infected with retrovirus constructs (vector or YAP) and puromycin was used to select for transduced cells. Cells were split and grown to ~60-75%% confluency at which point they were harvested for RNA. Vector vs. YAP comparison was done in duplicate.
2008-06-11 | E-GEOD-10196 | biostudies-arrayexpress
Project description:The two effector proteins of the Hippo signaling pathway, YAP and TAZ, play a pivotal role in the cellular homeostasis of podocytes and in the pathogenesis of focal segmental glomerulosclerosis (FSGS). We aim to unravel the unique and redundant functions of YAP and TAZ in the podocyte by identifying podocyte-specific interactors. We generated stable heat sensitive mouse podocytes (hsMPs) carrying a single copy integration of a transgenic construct expressing a flagged version of mouse Yap (3XFLAG.YAP), Taz (3XFLAG.TAZ) or Ruby (3XFLAG.RUBY) in the Rosa26 locus. To explore the interactome of YAP and TAZ in podocytes we immunoprecipitated the tagged proteins and characterized the co-immunoprecipitated protein complexes by mass spectrometry. Within the interactome analyses of the hsMPs, we identified shared and non-shared interacting proteins between YAP and TAZ. Among these identified proteins many well established interactors of YAP and TAZ were included, like proteins of the Tead family, different angiomotins or large tumor suppressor kinase 1 (Lats1). Strikingly, among the shared proteins were numerous proteins of the nuclear shuttling machinery, like importins (Ipo), exportins (Xpo), transportins (Tnpo) and nucleoporins (Nup) that form the nuclear pore complex (NPC), such as NUP107, NUP133, NUP205 and XPO5.
2024-01-26 | PXD040448 | Pride
Project description:Abstract Hippo pathway downstream effectors Yap and Taz play key roles in cell proliferation and regeneration, regulating gene expression especially via interaction with Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analysed Taz in vivo and ex vivo in comparison to Yap. Taz was expressed in activated satellite cells. siRNA knockdown or constitutive expression of wildtype or constitutively active TAZ mutants showed that TAZ promoted proliferation, a function that was shared with YAP. However, at later stages of myogenesis, TAZ also enhanced myogenic differentiation of myoblasts, whereas YAP inhibits such differentiation. Functionally, while muscle growth was mildly affected in Taz (gene symbol Wwtr1-/-) knockout mice, there were no overt effect on regeneration. However, conditional knockout of Yap in satellite cells of Pax7Cre-ERT2/+ : Yapflox/flox : Rosa26Lacz mice produced a marked regeneration deficit. To identify potential mechanisms, microarray analysis showed many common Taz/Yap targets, but Taz also regulates some genes independently of Yap, including myogenic genes such as Pax7, Myf5 and Myod1. Proteomic analysis of Yap/Taz revealed many common binding partners, but Taz also interacts with proteins distinct from Yap, that are mainly involved in myogenesis and aspects of cytoskeleton organization. Neither TAZ nor YAP bind members of the Wnt destruction complex but both extensively changed expression of Wnt and Wnt-cross talking genes with known roles in myogenesis. Finally, TAZ operates through Tead4 to enhance myogenic differentiation. In summary, Taz and Yap have overlapping functions in promoting myoblast proliferation but Taz then switches to promote myogenic differentiation.
2017-06-13 | PXD005751 | Pride
Project description:Human cancer is often caused by dysfunctional developmental pathways, but such mechanisms do not always present clear opportunities for therapeutic intervention. This is exemplified by the Hippo tumor suppressor pathway, which is comprised of a kinase module that restrains the function of YAP/TAZ transcriptional coactivators; a pathway that becomes dysregulated in a wide array of human cancers. Hence, YAP/TAZ hyperactivation is a tumorigenic mechanism and a validated therapeutic target in oncology. In this study, we used a paralog co-targeting genetic screening strategy to identify the kinases MARK2/3 as co-dependencies of YAP/TAZ in diverse cancer contexts. We use biochemical and epistasis experiments to show that MARK2/3 phosphorylate and inhibit the activity of Hippo pathway components NF2, MST1/2, and MAP4Ks, which leads to indirect upstream control of LATS1/2 activity. In addition, MARK2/3 directly phosphorylate YAP/TAZ to shield these coactivators from LATS1/2-mediated inhibition. The net consequence of this multi-level regulation is that YAP/TAZ-dependent human cancers have an absolute requirement for MARK2/3 catalytic activity to sustain tumor cell proliferation and viability. To simulate therapeutic targeting of MARK2/3 in vivo, we adapted the EPIYA-repeat region of the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show exerts potent anti-tumor activity via on-target mechanisms. Together, these findings reveal MARK2/3 as an obligate catalytic requirement for YAP/TAZ function in human cancer; kinase targets that may allow for novel pharmacology that restores Hippo-mediated tumor suppression.
2024-07-25 | PXD044829 | Pride
Project description:Human cancer is often caused by dysfunctional developmental pathways, but such mechanisms do not always present clear opportunities for therapeutic intervention. This is exemplified by the Hippo tumor suppressor pathway, which is comprised of a kinase module that restrains the function of YAP/TAZ transcriptional coactivators; a pathway that becomes dysregulated in a wide array of human cancers. Hence, YAP/TAZ hyperactivation is a tumorigenic mechanism and a validated therapeutic target in oncology. In this study, we used a paralog co-targeting genetic screening strategy to identify the kinases MARK2/3 as co-dependencies of YAP/TAZ in diverse cancer contexts. We use biochemical and epistasis experiments to show that MARK2/3 phosphorylate and inhibit the activity of Hippo pathway components NF2, MST1/2, and MAP4Ks, which leads to indirect upstream control of LATS1/2 activity. In addition, MARK2/3 directly phosphorylate YAP/TAZ to shield these coactivators from LATS1/2-mediated inhibition. The net consequence of this multi-level regulation is that YAP/TAZ-dependent human cancers have an absolute requirement for MARK2/3 catalytic activity to sustain tumor cell proliferation and viability. To simulate therapeutic targeting of MARK2/3 in vivo, we adapted the EPIYA-repeat region of the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show exerts potent anti-tumor activity via on-target mechanisms. Together, these findings reveal MARK2/3 as an obligate catalytic requirement for YAP/TAZ function in human cancer; kinase targets that may allow for novel pharmacology that restores Hippo-mediated tumor suppression.
2024-07-25 | PXD054192 | Pride
Project description:Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that transcriptional coregulators YAP and TAZ mediate the crosstalk between fat mass and leptin levels to maintain metabolic homeostasis. Activating YAP/TAZ in adipocytes by Lats1 and Lats2 deletion results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells. Surprisingly, Lats1/2 knockout mice did not exhibit lipodystrophy-related metabolic dysfunction, attributed to a paradoxical increase in circulating leptin levels. Mechanistically, YAP/TAZ-TEAD signaling upregulates leptin expression by directly binding an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is linked to, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ plays an essential role in coordinating adipose storage capacity and systemic energy balance through dual control of adipocyte plasticity and leptin gene transcription.
2024-03-21 | GSE261825 | GEO
Project description:Purpose: We aimed to elucidate the unique consequences of YAP/TAZ activation in pancreatic ductal cells. Methods: We isolated RNA from Lats1 and Lats2 double knockout ductal cells from Lats1fl/fl; Lats2fl/fl; Sox9-CreER mice. Results: Oncogenic activation of YAP in ductal cells lead to the rapid development of carcinoma in situ with microinvasion.
2020-09-17 | GSE129045 | GEO
Project description:YAP is an oncogene and an inducer of Epithelial-to-Mesenchymal Transition (EMT). We used microarrays to detail the global program of gene expression to identify YAP target genes. PUBLICATION ABSTRACT: The Hippo pathway defines a novel signaling cascade regulating cell proliferation and survival in Drosophila, which involves the negative regulation of the transcriptional coactivator Yorkie by the kinases Hippo and Warts. We have recently shown that the human ortholog of Yorkie, YAP, maps to a minimal amplification locus in mouse and human cancers, and that it mediates dramatic transforming activity in MCF10A primary mammary epithelial cells. Here we show that LATS proteins (mammalian orthologs of Warts) interact directly with YAP in mammalian cells and that ectopic expression of LATS1, but not LATS2, effectively suppresses the YAP phenotypes. Furthermore, shRNA-mediated knockdown of LATS1 phenocopies YAP overexpression. Since this effect can be suppressed by simultaneous YAP knockdown, it suggests that YAP is the primary target of LATS1 in mammalian cells. Expression profiling of genes induced by ectopic expression of YAP or by knockdown of LATS1 reveals a subset of potential Hippo pathway targets implicated in epithelial-to-mesenchymal transition (EMT), suggesting that this is a key feature of YAP signaling in mammalian cells. Keywords: vector vs. YAP comparison
2008-01-31 | GSE10196 | GEO
Project description:YAP1 (Yes-associated protein 1) and TAZ (transcriptional coactivator with PDZ-binding motif, or WWTR1) are nucleo-cytoplasmic shuttling proteins that can function in the nucleus as transcriptional coactivators. Their role in regulating gene transcription has been so far mainly investigated by overexpressing YAP1 or TAZ, while here we sought to determine which genes are regulated by endogenous levels of YAP/TAZ. To this end, we compared MCF10A cells transfected with a control non-targeting siRNA to cells transfected with two independent mixes of siRNA targeting both YAP and TAZ.
2015-03-23 | GSE59230 | GEO