scholarly journals Pits and CtBP control tissue growth in Drosophila melanogaster with the Hippo pathway transcription repressor, Tgi

2019 ◽  
Author(s):  
Joseph H.A. Vissers ◽  
Lucas G. Dent ◽  
Colin House ◽  
Shu Kondo ◽  
Kieran F. Harvey
Keyword(s):  
Cell Fate ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Affinity Purification ◽  
Hippo Pathway ◽  
Transcriptional Response ◽  
Size Control ◽  
Tissue Growth ◽  
Organ Size ◽  
The Hippo Pathway

ABSTRACTThe Hippo pathway is an evolutionary conserved signalling network that regulates organ size, cell fate control and tumorigenesis. In the context of organ size control, the pathway incorporates a large variety of cellular cues such as cell polarity and adhesion into an integrated transcriptional response. The central Hippo signalling effector is the transcriptional co-activator Yorkie, which controls gene expression in partnership with different transcription factors, most notably Scalloped. When it is not activated by Yorkie, Scalloped can act as a repressor of transcription, at least in part due to its interaction with the corepressor protein Tgi. The mechanism by which Tgi represses transcription is incompletely understood and therefore we sought to identify proteins that potentially operate together with it. Using an affinity purification and mass-spectrometry approach we identified Pits and CtBP as Tgi-interacting proteins, both of which have been linked to transcriptional repression. Both Pits and CtBP were required for Tgi to suppress the growth of the D. melanogaster eye and CtBP loss suppressed the undergrowth of yorkie mutant eye tissue. Furthermore, as reported previously for Tgi, overexpression of Pits suppressed transcription of Hippo pathway target genes. These findings suggest that Tgi might operate together with Pits and CtBP to repress transcription of genes that normally promote tissue growth. The human orthologues of Tgi, CtBP and Pits (VGLL4, CTBP2 and IRF2BP2) physically and functionally interact to control transcription, implying that the mechanism by which these proteins control transcriptional repression is conserved throughout evolution.

scholarly journals Pits and CtBP Control Tissue Growth in Drosophila melanogaster with the Hippo Pathway Transcription Repressor Tgi

Genetics ◽  
2020 ◽  
Vol 215 (1) ◽  
pp. 117-128
Author(s):  
Joseph H. A. Vissers ◽  
Lucas G. Dent ◽  
Colin M. House ◽  
Shu Kondo ◽  
Kieran F. Harvey
Keyword(s):  
Drosophila Melanogaster ◽  
Cell Fate ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Affinity Purification ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Organ Size ◽  
Link Type ◽  
The Hippo Pathway

The Hippo pathway is an evolutionarily conserved signaling network that regulates organ size, cell fate, and tumorigenesis. In the context of organ size control, the pathway incorporates a large variety of cellular cues, such as cell polarity and adhesion, into an integrated transcriptional response. The central Hippo signaling effector is the transcriptional coactivator Yorkie, which controls gene expression in partnership with different transcription factors, most notably Scalloped. When it is not activated by Yorkie, Scalloped can act as a repressor of transcription, at least in part due to its interaction with the corepressor protein Tgi. The mechanism by which Tgi represses transcription is incompletely understood, and therefore we sought to identify proteins that potentially operate together with Tgi. Using an affinity purification and mass-spectrometry approach we identified Pits and CtBP as Tgi-interacting proteins, both of which have been linked to transcriptional repression. Both Pits and CtBP were required for Tgi to suppress the growth of the Drosophila melanogaster eye and CtBP loss suppressed the undergrowth of yorkie mutant eye tissue. Furthermore, as reported previously for Tgi, overexpression of Pits repressed transcription of Hippo pathway target genes. These findings suggest that Tgi might operate together with Pits and CtBP to repress transcription of genes that normally promote tissue growth. The human orthologs of Tgi, CtBP, and Pits (VGLL4, CTBP2, and IRF2BP2) have previously been shown to physically and functionally interact to control transcription, implying that the mechanism by which these proteins control transcriptional repression is conserved throughout evolution.

scholarly journals Localized JNK signaling regulates organ size during development

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Helen Rankin Willsey ◽  
Xiaoyan Zheng ◽  
José Carlos Pastor-Pareja ◽  
A Jeremy Willsey ◽  
Philip A Beachy ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Hippo Pathway ◽  
Size Control ◽  
Organ Size ◽  
Control Mechanisms ◽  
Cancer Therapies ◽  
Independent Manner ◽  
Jnk Signaling ◽  
New Strategy ◽  
The Hippo Pathway

A fundamental question of biology is what determines organ size. Despite demonstrations that factors within organs determine their sizes, intrinsic size control mechanisms remain elusive. Here we show that Drosophila wing size is regulated by JNK signaling during development. JNK is active in a stripe along the center of developing wings, and modulating JNK signaling within this stripe changes organ size. This JNK stripe influences proliferation in a non-canonical, Jun-independent manner by inhibiting the Hippo pathway. Localized JNK activity is established by Hedgehog signaling, where Ci elevates dTRAF1 expression. As the dTRAF1 homolog, TRAF4, is amplified in numerous cancers, these findings provide a new mechanism for how the Hedgehog pathway could contribute to tumorigenesis, and, more importantly, provides a new strategy for cancer therapies. Finally, modulation of JNK signaling centers in developing antennae and legs changes their sizes, suggesting a more generalizable role for JNK signaling in developmental organ size control.

scholarly journals Usp10 Modulates the Hippo Pathway by Deubiquitinating and Stabilizing the Transcriptional Coactivator Yorkie

2019 ◽  
Vol 20 (23) ◽  
pp. 6013
Author(s):  
Yang Gao ◽  
Xiaoting Zhang ◽  
Lijuan Xiao ◽  
Chaojun Zhai ◽  
Tao Yi ◽  
...  
Keyword(s):  
Target Genes ◽  
Hippo Pathway ◽  
Size Control ◽  
Deubiquitinating Enzyme ◽  
Hippo Signaling ◽  
Evolutionarily Conserved ◽  
Specific Protease ◽  
Wing Discs ◽  
The Hippo Pathway

The Hippo signaling pathway is an evolutionarily conserved regulator that plays important roles in organ size control, homeostasis, and tumorigenesis. As the key effector of the Hippo pathway, Yorkie (Yki) binds to transcription factor Scalloped (Sd) and promotes the expression of target genes, leading to cell proliferation and inhibition of apoptosis. Thus, it is of great significance to understand the regulatory mechanism for Yki protein turnover. Here, we provide evidence that the deubiquitinating enzyme ubiquitin-specific protease 10 (Usp10) binds Yki to counteract Yki ubiquitination and stabilize Yki protein in Drosophila S2 cells. The results in Drosophila wing discs indicate that silence of Usp10 decreases the transcription of target genes of the Hippo pathway by reducing Yki protein. In vivo functional analysis ulteriorly showed that Usp10 upregulates the Yki activity in Drosophila eyes. These findings uncover Usp10 as a novel Hippo pathway modulator and provide a new insight into the regulation of Yki protein stability and activity.

scholarly journals The Hippo Pathway: Biology and Pathophysiology

2019 ◽  
Vol 88 (1) ◽  
pp. 577-604 ◽  
Author(s):  
Shenghong Ma ◽  
Zhipeng Meng ◽  
Rui Chen ◽  
Kun-Liang Guan
Keyword(s):  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Size Control ◽  
Tissue Growth ◽  
Cell Contact ◽  
Energy Status ◽  
Downstream Effectors ◽  
Kinase Cascade ◽  
Fate Decision ◽  
The Hippo Pathway

The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size control, and regeneration. The core of the Hippo pathway in mammals consists of a kinase cascade, MST1/2 and LATS1/2, as well as downstream effectors, transcriptional coactivators YAP and TAZ. These core components of the Hippo pathway control transcriptional programs involved in cell proliferation, survival, mobility, stemness, and differentiation. The Hippo pathway is tightly regulated by both intrinsic and extrinsic signals, such as mechanical force, cell–cell contact, polarity, energy status, stress, and many diffusible hormonal factors, the majority of which act through G protein–coupled receptors. Here, we review the current understanding of molecular mechanisms by which signals regulate the Hippo pathway with an emphasis on mechanotransduction and the effects of this pathway on basic biology and human diseases.

scholarly journals The Hippo pathway component Wwc2 is a key regulator of embryonic development and angiogenesis in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Anke Hermann ◽  
Guangming Wu ◽  
Pavel I. Nedvetsky ◽  
Viktoria C. Brücher ◽  
Charlotte Egbring ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Cell Fate ◽  
Target Genes ◽  
Hippo Pathway ◽  
Growth Control ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Large Tumor ◽  
Organ Growth ◽  
The Hippo Pathway

AbstractThe WW-and-C2-domain-containing (WWC) protein family is involved in the regulation of cell differentiation, cell proliferation, and organ growth control. As upstream components of the Hippo signaling pathway, WWC proteins activate the Large tumor suppressor (LATS) kinase that in turn phosphorylates Yes-associated protein (YAP) and its paralog Transcriptional coactivator-with-PDZ-binding motif (TAZ) preventing their nuclear import and transcriptional activity. Inhibition of WWC expression leads to downregulation of the Hippo pathway, increased expression of YAP/TAZ target genes and enhanced organ growth. In mice, a ubiquitous Wwc1 knockout (KO) induces a mild neurological phenotype with no impact on embryogenesis or organ growth. In contrast, we could show here that ubiquitous deletion of Wwc2 in mice leads to early embryonic lethality. Wwc2 KO embryos display growth retardation, a disturbed placenta development, impaired vascularization, and finally embryonic death. A whole-transcriptome analysis of embryos lacking Wwc2 revealed a massive deregulation of gene expression with impact on cell fate determination, cell metabolism, and angiogenesis. Consequently, a perinatal, endothelial-specific Wwc2 KO in mice led to disturbed vessel formation and vascular hypersprouting in the retina. In summary, our data elucidate a novel role for Wwc2 as a key regulator in early embryonic development and sprouting angiogenesis in mice.

scholarly journals The miRNA bantam regulates growth and tumorigenesis by repressing the cell cycle regulator tribbles

2019 ◽  
Vol 2 (4) ◽  
pp. e201900381 ◽  
Author(s):  
Stephan U Gerlach ◽  
Moritz Sander ◽  
Shilin Song ◽  
Héctor Herranz
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Target Genes ◽  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Tumor Formation ◽  
Hippo Signaling ◽  
Cell Cycle Regulators ◽  
The Hippo Pathway

One of the fundamental issues in biology is understanding how organ size is controlled. Tissue growth has to be carefully regulated to generate well-functioning organs, and defects in growth control can result in tumor formation. The Hippo signaling pathway is a universal growth regulator and has been implicated in cancer. In Drosophila, the Hippo pathway acts through the miRNA bantam to regulate cell proliferation and apoptosis. Even though the bantam targets regulating apoptosis have been determined, the target genes controlling proliferation have not been identified thus far. In this study, we identify the gene tribbles as a direct bantam target gene. Tribbles limits cell proliferation by suppressing G2/M transition. We show that tribbles regulation by bantam is central in controlling tissue growth and tumorigenesis. We expand our study to other cell cycle regulators and show that deregulated G2/M transition can collaborate with oncogene activation driving tumor formation.

scholarly journals The Hippo pathway oncoprotein YAP promotes melanoma cell invasion and spontaneous metastasis

2019 ◽  
Author(s):  
Xiaomeng Zhang ◽  
Lie Yang ◽  
Pacman Szeto ◽  
Youfang Zhang ◽  
Kaushalya Amarasinghe ◽  
...  
Keyword(s):  
Cell Fate ◽  
Melanoma Cell ◽  
Cell Invasion ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Expression Profiles ◽  
Hippo Pathway ◽  
Melanoma Metastasis ◽  
The Hippo Pathway

ABSTRACTMelanoma is a deadly form of skin cancer that accounts for a disproportionally large proportion of cancer-related deaths in younger people. Compared to most other skin cancers, a feature of melanoma is its high metastatic capacity, although molecular mechanisms that confer this are not well understood. The Hippo pathway is a key regulator of organ growth and cell fate that is deregulated in many cancers. To analyse the Hippo pathway in cutaneous melanoma, we generated a transcriptional signature of pathway activity in melanoma cells. Hippo-mediated transcriptional activity varied in melanoma cell lines but failed to cluster with known genetic drivers of melanomagenesis such as BRAF and NRAS mutation status. Instead, it correlated strongly with published gene expression profiles linked to melanoma cell invasiveness. Consistent with this, the central Hippo oncogene, YAP, was both necessary and sufficient for melanoma cell invasion in vitro. In in vivo murine studies, YAP promoted spontaneous melanoma metastasis, whilst the growth of YAP-expressing primary tumours was impeded. Finally, we identified the YAP target genes AXL, THBS1 and CYR61 as key mediators of YAP-induced melanoma cell invasion. These data suggest that the Hippo pathway is a critical regulator of melanoma metastasis.

scholarly journals Cultured cells and wing disc size of silkworm can be controlled by the Hippo pathway

Open Biology ◽  
2018 ◽  
Vol 8 (7) ◽  
pp. 180029 ◽  
Author(s):  
Zi Liang ◽  
Yahong Lu ◽  
Ying Qian ◽  
Liyuan Zhu ◽  
Sulan Kuang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cultured Cells ◽  
Hippo Pathway ◽  
Size Control ◽  
Wing Disc ◽  
Organ Size ◽  
Promote Cell Proliferation ◽  
A Cell ◽  
The Hippo Pathway ◽  
Disc Size

Hippo signalling represents a cell proliferation and organ-size control pathway. Yorki (Yki), a component of the Hippo pathway, induces the transcription of a number of targets that promote cell proliferation and survival. The functions of Yki have been characterized in Drosophila and mammals, while there are few reports on silkworm, Bombyx mori . In the present study, we found that BmYki3 facilitates cell migration and cell division, and enlarges the cultured cell and wing disc size. Co-immunoprecipitation results indicated that BmYki3 may interact with thymosin, E3 ubiquitin-protein ligase, protein kinase ASK1, dedicator of cytokinesis protein 1, calcium-independent phospholipase A2 and beta-spectrin. RNA-seq results indicated that 4444 genes were upregulated and 10 291 genes were downregulated after BmYki3 was overexpressed in the cultured cells. GO annotation indicated that the up/downregulated genes were enriched in 268/382 GO terms ( p < 0.01); KEGG analysis showed that the up/downregulated genes were enriched in 49/101 pathways. These findings provided novel information to understand the functions of BmYki3 in a cell proliferation and organ-size control pathway.

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