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Protein O-GlcNAcylation coupled to Hippo signaling drives vascular dysfunction in diabetic retinopathy [9A]

ABSTRACT: Metabolic disorder is emerging as a crucial contributor to the pathogenesis of diabetic vascular complications including diabetic retinopathy (DR), the leading cause of blindness in the working-age population. Yet, the underlying molecular mechanisms of how the disturbed metabolic homeostasis contribute to vascular dysfunction in DR remain elusive. O-GlcNAcylation modification act as a nutrient sensor particularly sensitive to ambient glucose. Here, we observed pronounced O-GlcNAc elevation in retina endothelial cells (ECs) of DR patients and mouse models. Endothelial-specific depletion or pharmacological inhibition of O-GlcNAc transferase efficiently mitigated vascular dysfunctions. Mechanistically, we found that YAP/TAZ, key effectors of the Hippo pathway, are O-GlcNAcylated in DR. We identified Thr383 as an O-GlcNAc site on YAP, which inhibits its phosphorylation at Ser397, leading to its stabilization and activation. Consequently, highly activated YAP/TAZ, promotes vascular dysfunction by inducing a pro-angiogenic and glucose metabolic transcriptional program. These findings emphasize the critical role of O-GlcNAc-Hippo axis in DR pathogenesis and suggest its unique potential as a therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266072 | GEO | 2024/09/24

REPOSITORIES: GEO

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Protein O-GlcNAcylation coupled to Hippo signaling drives vascular dysfunction in diabetic retinopathy [3A]

Project description:Metabolic disorder is emerging as a crucial contributor to the pathogenesis of diabetic vascular complications including diabetic retinopathy (DR), the leading cause of blindness in the working-age population. Yet, the underlying molecular mechanisms of how the disturbed metabolic homeostasis contribute to vascular dysfunction in DR remain elusive. O-GlcNAcylation modification act as a nutrient sensor particularly sensitive to ambient glucose. Here, we observed pronounced O-GlcNAc elevation in retina endothelial cells (ECs) of DR patients and mouse models. Endothelial-specific depletion or pharmacological inhibition of O-GlcNAc transferase efficiently mitigated vascular dysfunctions. Mechanistically, we found that YAP/TAZ, key effectors of the Hippo pathway, are O-GlcNAcylated in DR. We identified Thr383 as an O-GlcNAc site on YAP, which inhibits its phosphorylation at Ser397, leading to its stabilization and activation. Consequently, highly activated YAP/TAZ, promotes vascular dysfunction by inducing a pro-angiogenic and glucose metabolic transcriptional program. These findings emphasize the critical role of O-GlcNAc-Hippo axis in DR pathogenesis and suggest its unique potential as a therapeutic target.

2024-09-24 | GSE266071 | GEO

Hyperactivation of YAP/TAZ drives alterations in mesangial cells through stabilization of N-MYC in diabetic nephropathy

Project description:Mesangial cells (MCs) in the kidney are central to maintaining glomerular integrity, and their impairment leads to major glomerular diseases including diabetic nephropathy (DN). Although high blood glucose elicits abnormal alterations in MCs, the underlying molecular mechanism is poorly understood. Here, we show that YAP and TAZ, the final effectors of the Hippo pathway, are highly increased in MCs of patients with DN and of Zucker diabetic fatty rats. Moreover, high glucose directly induces activation of YAP/TAZ through the canonical Hippo pathway in cultured MCs. Hyperactivation of YAP/TAZ in mouse model MCs recapitulates the hallmarks of DN, including excessive proliferation of MCs and extracellular matrix deposition, endothelial cell impairment, glomerular sclerosis, albuminuria, and reduced glomerular filtration rate. Mechanistically, activated YAP/TAZ bind and stabilize N-Myc protein, one of the Myc family of oncogenes. N-Myc stabilization leads to aberrant enhancement of its transcriptional activity and eventually to MC impairments and DN pathogenesis. Together, these findings shed light on how high blood glucose in diabetes mellitus leads to DN and support a rationale that lowering blood glucose in diabetes mellitus could delay DN pathogenesis.

2022-02-01 | GSE195751 | GEO

Regulation of gene expression by the Hippo effectors, Taz and Yap, in muscle stem cells

Project description:The Hippo pathway downstream effectors, Yap and Taz, play key roles in cell proliferation and tissue growth, regulating gene expression especially via interaction with Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analysed gene expression changes driven by Taz and compared these to Yap mediated changes to the transcriptome by measurement of gene expression on Affymetrix microarrays. To interrogate overlapping and unique transcriptional changes driven by these Hippo effectors, satellite cell-derived myoblasts were transduced with constitutively active TAZ S89A or YAP S127A retrovirus for 24h or 48h, with empty retrovirus as control. Triplicate microarray analyses of empty vector controls, hYAP1 S127A and TAZ S89A transgenic primary myoblasts were conducted.

2017-06-20 | E-MTAB-5395 | biostudies-arrayexpress

The effect of YAP/TAZ knockdown on the intestinal epithelium

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A YAP/TAZ-TEAD signaling module links endothelial nutrient acquisition to angiogenic growth

Project description:Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue's metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are dictated by YAP/TAZ-TEAD – a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2, and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fueling nutrient mTORC1 signaling. By orchestrating the transcription of a repertoire of cell-surface transporters, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 pathway activation. Dissociating mTORC1 from these nutrient inputs – elicited by the loss of Rag GTPases – inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. These findings define a pivotal role for YAP/TAZ-TEAD in steering endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.

2022-05-08 | PXD026872 | Pride

Transcriptional targets of Hippo signaling in mammalian cells

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

Aortic samples of inducible vascular smooth muscle specific KO of YAP/TAZ

Project description:YAP and TAZ are transcriptional co-activators and downstream effectors of the Hippo pathway, which play crucial roles in organ size control and cancer pathogenesis. Genetic deletion of YAP/TAZ has revealed their critical importance for embryonic development of the heart, vasculature and gastrointestinal mesenchyme. The aim of this study was to determine the long term role of YAP/TAZ in adult vascular smooth muscle in vivo. We used the novel Itga8-CreERT2 mouse for deletion of YAP/TAZ (i8-Y/T-KO).

2023-08-13 | GSE240233 | GEO

MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer

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

MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer (part2)

2024-07-25 | PXD054192 | Pride

Muscle stems cell LC-MS - Common and Distinctive Functions of the Hippo Effectors Taz and Yap in Skeletal Muscle Stem Cell Function

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

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