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Development of an improved inhibitor of Lats Kinases to promote regeneration of mammalian organs

ABSTRACT: Development of an improved inhibitor of Lats Kinases to promote regeneration of mammalian organs

PROVIDER: PRJNA804393 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17933086.fastq.gz	Fastqsanger.gz
	SRR17933087.fastq.gz	Fastqsanger.gz
	SRR17933088.fastq.gz	Fastqsanger.gz
	SRR17933089.fastq.gz	Fastqsanger.gz
	SRR17933090.fastq.gz	Fastqsanger.gz

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Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs.

Project description:The Hippo signaling pathway acts as a brake on regeneration in many tissues. This cascade of kinases culminates in the phosphorylation of the transcriptional cofactors Yap and Taz, whose concentration in the nucleus consequently remains low. Various types of cellular signals can reduce phosphorylation, however, resulting in the accumulation of Yap and Taz in the nucleus and subsequently in mitosis. We earlier identified a small molecule, TRULI, that blocks the final kinases in the pathway, Lats1 and Lats2, and thus elicits proliferation of several cell types that are ordinarily postmitotic and aids regeneration in mammals. In the present study, we present the results of chemical modification of the original compound and demonstrate that a derivative, TDI-011536, is an effective blocker of Lats kinases in vitro at nanomolar concentrations. The compound fosters extensive proliferation in retinal organoids derived from human induced pluripotent stem cells. Intraperitoneal administration of the substance to mice suppresses Yap phosphorylation for several hours and induces transcriptional activation of Yap target genes in the heart, liver, and skin. Moreover, the compound initiates the proliferation of cardiomyocytes in adult mice following cardiac cryolesions. After further chemical refinement, related compounds might prove useful in protective and regenerative therapies.

| S-EPMC9282237 | biostudies-literature

Development of an improved inhibitor of Lats Kinases to promote regeneration of mammalian organs

Project description:To confirm that treatment with TDI‑011536 activates Yap in vivo, we collected liver and heart tissue for RNA sequencing four hours after IP injection at 200 mg/kg

2022-07-06 | GSE196322 | GEO

LATS kinase-mediated selective disruption of CTCF genomic binding

Project description:We identified CTCF as a substrate of the LATS kinases. Under cellular stress conditions that activated LATS, CTCF was phosphorylated in a LATS-dependent manner and lost DNA-binding activity. LATS signaling target genes resided in CTCF-mediated insulated neighborhoods and depended on such chromatin organization to sustain their expression. Genome-wide CTCF DNA-binding profiling revealed that metabolic stress reduced CTCF occupancy specifically at a small subset of CTCF-binding sites that encompassed many LATS target genes and were most significantly associated with LATS signaling. Dissociation of CTCF from LATS target genes disrupted corresponding CTCF-mediated chromatin domains and downregulated LATS target gene expression.

2020-03-09 | GSE114319 | GEO

Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

Project description:Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

| PRJNA624890 | ENA

LATS regulates heavy metal response

Project description:LATS regulates heavy metal response

| PRJNA685123 | ENA

Microarray of primary human breast cells with or without Hippo kinases LATS1/2

Project description:Perturbation of the tightly regulated dynamic process of cell fate underlies many human diseases. The molecular mechanisms regulating breast cell fate in the hierarchically organized luminal and basal lineages of breast epithelium remain largely elusive. We performed a high-content confocal image-based shRNA screen for regulators of primary human breast cell fate. Inhibition of the Hippo kinases LATS was found to promote luminal fate and increase the number of progenitors, which is a paradox given that Hippo effectors YAP/TAZ have been associated with basal fate. Mechanistically, LATS loss increases the activities of YAP/TAZ and ERα, which in concert control breast cell fate via intrinsic and paracrine effects. Reduced LATS expression is found in breast cancers with a poor prognosis; this diminishes the sensitivity of ERα-positive- and increases the sensitivity of ERα-negative cancers to endocrine therapy. Thus, in this study we have unraveled crosstalk between Hippo and estrogen signaling and shown that LATS loss triggers expansion of luminal progenitors, the highly suspected cell-of-origin in most breast cancers. In this dataset, we provide microarray gene expression analysis of normal breast epithelial cells, freshly dissociated from reduction mammoplasties, in which LATS1/2 were knocked down comparing it to non-targeting control expressing breast cells.

2017-01-27 | GSE61297 | GEO

Fission yeast NDR/LATS kinase Orb6 regulates exocytosis via phosphorylation of exocyst complex

Project description:NDR/LATS kinases regulate multiple aspects of cell polarity and morphogenesis from yeast to mammals, but few of their substrates are known. Fission yeast NDR/LATS kinase Orb6 has been proposed to control cell polarity via spatial regulation of Gef1, a guanine nucleotide exchange factor for the small GTPase Cdc42. Here we show that Orb6 plays a critical role as a positive regulator of exocytosis, independent of Gef1. Through Orb6 inhibition in vivo and quantitative global phosphoproteomics, we identify several proteins involved in membrane trafficking as Orb6 targets, and we confirm Sec3 and Sec5, conserved components of the exocyst complex, as substrates of Orb6 both in vivo and in vitro. Our results suggest that Orb6 kinase activity is crucial for exocyst localization to actively-growing cell tips and for exocyst activity during septum dissolution after cytokinesis. We further show that Orb6 phosphorylation of Sec3 serine-201 contributes to exocyst function in parallel with exocyst protein Exo70. We propose that Orb6 contributes to polarized growth by regulating membrane trafficking at multiple levels.

2019-01-31 | PXD009408 | Pride

Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues.

Project description:Hippo signaling is an evolutionarily conserved pathway that restricts growth and regeneration predominantly by suppressing the activity of the transcriptional coactivator Yap. Using a high-throughput phenotypic screen, we identified a potent and non-toxic activator of Yap. In vitro kinase assays show that the compound acts as an ATP-competitive inhibitor of Lats kinases-the core enzymes in Hippo signaling. The substance prevents Yap phosphorylation and induces proliferation of supporting cells in the murine inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. RNA sequencing indicates that the inhibitor reversibly activates the expression of transcriptional Yap targets: upon withdrawal, a subset of supporting-cell progeny exits the cell cycle and upregulates genes characteristic of sensory hair cells. Our results suggest that the pharmacological inhibition of Lats kinases may promote initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear.

| S-EPMC8149661 | biostudies-literature

Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

Project description:We report on the gene expression changes associated with Lats1/2 inhibition in supporting cells of the vestibular inner ear sensory epithelium

2020-04-13 | GSE148528 | GEO

Effect of NIBR-LTSi treatment on gene expression in mouse intestinal organoids

Project description:The YAP/Hippo pathway is a key regulator of organ growth and size regulation and is involved in safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. We report on the gene expression changes associated with YAP activation by the selective small molecule LATS kinase inhibitor NIBR-LTSi in mouse intestinal organoids. We show that, LATS-LTSi activates YAP signalling, promotes proliferation, induces a regenerative phenotype and blocks differentiation.

2024-03-07 | GSE240969 | GEO

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