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P120 RasGAP and ZO-2 promote the tumor suppressor function of p190A RhoGAP

ABSTRACT: ARHGAP35 encoding p190A RhoGAP (p190A) was identified by GWAS as a major human cancer gene. Our published studies have determined that p190A is a tumor suppressor that activates the canonical Hippo pathway. To elucidate how p190A signals in this context, we performed mass spectrometry to identify p190A binding proteins. Two interactors were identified significantly more frequently than others: p120 RasGAP (p120) and ZO-1. Originally p190A was cloned via its direct binding to p120, hence validating our approach. In addition, we found that p190A also binds to ZO-2. The interaction of p190A with ZO-2 is dependent on p120, thus suggesting formation of a ternary complex. Next, we determine that both p120 and ZO-2, but not ZO-1, are necessary for p190A to activate LATS kinases and suppress tumorigenesis in a xenograft mouse model. Moreover, the interactions with p120 and ZO-2 are essential for transcriptional modulation by p190A, including the CDH1 gene encoding E-cadherin, which we previously have demonstrated is essential for p190A signaling. Collectively, this work identifies a novel tumor suppressor interactome of p190A, which includes ZO-2, an established constituent of the Hippo pathway, and p120, which in spite of its strong association with Ras signaling, is essential for p190A to activate LATS kinases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212619 | GEO | 2023/04/15

REPOSITORIES: GEO

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p190 RhoGAP mediates contact inhibition of cell proliferation by repressing YAP1-mediated gene transcription

Project description:Recently, ARHGAP35 encoding p190A RhoGAP was unexpectedly found to rank among the 20-30 most frequently mutated genes in human cancer. The spectrum of mutations in ARHGAP35 is consistent with that of a tumor suppressor, but the underlying mechanisms are not well understood. In this work we sought to elucidate functions for p190A RhoGAP (p190A) and its isoform p190B RhoGAP (p190B) that might confer tumor suppressor capacities in epithelial cells. We establish an essential role for p190A and p190B to mediate contact inhibition of cell proliferation (CIP). Both p190A and p190B localize in part to adherens junctions, which is consistent with a role in CIP. Using an unbiased approach, we determine that p190A and p190B repress expression of a cassette of genes that are modulated by the Hippo pathway. Moreover, we demonstrate that p190A and p190B promote activation of LATS kinases and inhibit translocation of the Hippo transducer YAP to the nucleus. Next, we validate that expression of an activated form of YAP induces a gene signature with significant similarities to that of cells depleted of p190A and p190B expression. Furthermore, we establish that p190A and p190B promote CIP by repressing YAP-TEAD-mediated gene transcription. Collectively, our results demonstrate that p190 RhoGAPs serve as activators of the Hippo pathway, which is widely implicated in CIP. Our work suggests that ARHGAP35 belongs to group of tumor suppressor genes, including AJUBA, CDH1, and NF2, with gene products that localize to cell-cell junctions and modulate the activity MST/LATS complex.

2016-12-30 | GSE75099 | 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

Regulation of the Hippo pathway by phosphoinositol transfer protein (PITP) and phosphoinositides

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

Expression analysis of a preinvasive pancreatic cancer mouse model with and without p120 catenin

Project description:Pancreatic cancer is one of the most deadly cancers with a 5 year survival rate of about 5%. Therapeutic options are limited, especially for patients that present with late state disease and metastasis. Although the metastatic burden of pancreatic cancer is usually high, little is known about the mechanisms that regulate delamination and dissemination of epithelial cells from preinvasive and malignant pancreatic lesions. Here, we used a preinvasive mouse model of pancreatic cancer to conditionally knockout p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high grade PanIN lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by activation of S1P/S1P2 signaling. Our results establish p120 catenin and S1P/S1P2 signaling as novel regulators of non-EMT mediated epithelial cell invasion in pancreatic neoplasia.

2016-07-25 | GSE68090 | GEO

Expression analysis of a preinvasive pancreatic cancer mouse model with and without p120 catenin

2016-07-25 | E-GEOD-68090 | biostudies-arrayexpress

p120-catenin differentially regulates cell migration by Rho-dependent intracellular and secreted signals

Project description:The Adherens Junction protein p120-catenin is implicated in the regulation of cadherin stability, cell migration and inflammatory responses in mammalian epithelial tissues. How these events are coordinated to promote wound repair is not understood. We show that p120-catenin regulates the intrinsic migratory properties or primary mouse keratinocytes, but also influences the migratory behavior of neighboring cells by secreted signals. These events are rooted in the ability of p120-catenin to regulate RhoA-GTPase activity, which leads to a two-tiered control of cell migration. One restrains cell motility via increase of actin stress fibers, reduction in integrin turnover, and an increase in focal adhesions robustness. The other is coupled to the secretion of inflammatory cytokines including Interleukin-24, which causally enhances randomized cell movements. Taken together, our results indicate that p120-RhoA-GTPase-mediated signaling can differentially regulate the migratory behavior of epidermal cells, which has potential implications for chronic wound responses and cancer.

2016-12-31 | GSE55019 | GEO

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

PI-5-P links the Hippo Pathway and PI5P4K signaling

Project description:The phosphoinositide PI-5-P is a signaling lipid that mediates cellular responses to oxidative stress and DNA damage, however it is unclear how PI-5-P participates in these processes. Intracellular pools of PI-5-P are regulated by PI5P-Kinases (PI5P4Ks), but how PI5P4K activity is controlled has also remained elusive. Here, we used an unbiased screen to discover the core Hippo pathway kinases MST1/2 phosphorylate and inhibit PI5P4K signaling in vitro and in cells. We further show PI5P4Ks regulate several Hippo/YAP-related phenotypes in human cells, such as the interaction between the key Hippo proteins MOB1-LATS, and the genetic program governing epithelial-to-mesenchymal transition. Mechanistically, we show that MOB1 binds PI-5-P with high specificity and potency, providing a signaling connection between the Hippo Pathway and PI5P4Ks. These discoveries shed new light on how these two important evolutionary conserved signaling pathways are integrated to regulate metazoan development and human disease.

2023-12-31 | GSE221217 | GEO

Transcriptome analysis of WWC2-deficient E11.5 embryos

Project description:The Hippo signaling pathway is known to regulate cell differentiation, proliferation and apoptosis. The WWC proteins, WWC1 and WWC2, positively regulate the Hippo pathway by the activation of the LATS kinases and the subsequent cytoplasmic translocation of YAP. The in vivo role of WWC2 has not been studied, yet. We could show, that the ubiquitous knockout of WWC2 in mice leads to placental defects, growth retardation, a disturbed angiogenesis and vascularization resulting in embryonic lethality at around E11.5. To further understand the function of WWC2 in the embryonic development, a transcriptome analysis by next generation sequencing was performed.

2021-06-28 | GSE116382 | GEO

Microarray of MCF10A cells with/without LATS1/2, expressing YAP/TAZ or ESR1 cDNA

Project description:Cell fate perturbations underlie many human diseases, including breast cancer. However, the regulation of breast cell fate remains largely elusive. The mammary gland epithelium consists of differentiated luminal epithelial and basal myoepithelial cells, as well as undifferentiated stem cells and more restricted progenitors. Breast cancer originates from this epithelium but the molecular mechanisms underlying breast epithelial hierarchy remain ill-defined. Mouse and human luminal cells express keratins (K)18, 8, 19 and/or estrogen receptor α (ERα) and progesterone receptor (PR), their basal counterparts express K5, 14 and/or p63 and/or α-smooth-muscle actin (α-SMA)4-6. In this study, using a high-content confocal image-based shRNA screen for tumor suppressors regulating human breast cell fate, we discovered that ablation of the Hippo kinases large tumor suppressor (LATS) 1 and 2, promoted luminal fate and increased the number of bipotent and luminal progenitors, the proposed cell-of-origin of most human breast cancers. Mechanistically, we discovered a crosstalk between Hippo and ERα signaling. In the presence of LATS, ERα was targeted for ubiquitination and proteasomal degradation. Loss of LATS stabilized ERα and Hippo effectors YAP/TAZ, which in concert control breast cell fate via intrinsic and paracrine mechanisms. Our findings uncover a novel non-canonical (i.e., YAP/TAZ-independent) effect of LATS in the regulation of human breast cell fate. 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.

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