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P190 RhoGAP mediates contact inhibition of cell proliferation by repressing YAP1-mediated gene transcription

ABSTRACT: 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.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE75099 | GEO | 2016/12/30

SECONDARY ACCESSION(S): PRJNA302442

REPOSITORIES: GEO

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p120 RasGAP and ZO-2 promote the tumor suppressor function of p190A RhoGAP

Project description: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.

2023-04-15 | GSE212619 | GEO

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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.

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2022-02-12 | GSE196262 | GEO

Transcription profiling by array of human MCF10A cells expressing YAP to identify the targets of the YAP oncogene

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

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.

2017-01-27 | GSE80055 | 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

A splicing switch of TEAD4 regulates Hippo-YAP signaling pathway to inhibit tumor proliferation

Project description:Splicing dysregulations extensively occur in cancers, yet the biological consequences of such alterations are mostly undefined. Here we report that the Hippo-YAP signaling, a key pathway that regulates cell proliferation and organ size, is under control of a new splicing switch. We show that TEAD4, the transcription factor that mediates Hippo-YAP signaling, undergoes alternative splicing facilitated by the tumor suppressor RBM4, producing a truncated isoform, TEAD4-S, which lacks N-terminal DNA-binding domain but maintains YAP-interaction domain. TEAD4-S is located in both nucleus and cytoplasm, acting as a dominant negative isoform to YAP activity. Consistently, TEAD4-S is reduced in cancer cells, and its re-expression suppresses cancer cell proliferation and migration, inhibiting tumor growth in xenograft mouse model. Furthermore, TEAD4-S is reduced in human cancers, and patients with elevated TEAD4-S levels have improved survival. Altogether these data reveal a novel RBM4-mediated splicing switch that serves to fine-tune Hippo-YAP pathway. Cell lines stably expressing YAP, YAP/TEAD4-S, YAP/TEAD4-FL, YAP/RBM4 and control vector were created, and the total RNA was purified from the cells using TRIzol reagents. The polyadenylated RNAs were purified for construction of sequencing library using kapa TruSeq Total RNA Sample Prep kits (UNC High Throughput Sequencing Facility).

2016-06-16 | E-GEOD-80372 | biostudies-arrayexpress

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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

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

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