Shavenbaby and Yorkie mediate Hippo signaling to protect adult stem cells from apoptosis

AbstractTo compensate for accumulating damages and cell death, adult homeostasis (e.g., body fluids and secretion) requires organ regeneration, operated by long-lived stem cells. How stem cells can survive throughout the animal life yet remains poorly understood. Here we show that the transcription factor Shavenbaby (Svb, OvoL in vertebrates) is expressed in renal/nephric stem cells (RNSCs) ofDrosophilaand required for their maintenance during adulthood. As recently shown in embryos, Svb function in adult RNSCs further needs a post-translational processing mediated by Polished rice (Pri) smORF peptides and impairing Svb function leads to RNSC apoptosis. We show that Svb interacts both genetically and physically with Yorkie (YAP/TAZ in vertebrates), a nuclear effector of the Hippo pathway, to activate the expression of the inhibitor of apoptosisDIAP1. These data therefore identify Svb as a novel nuclear effector in the Hippo pathway, critical for the survival of adult somatic stem cells.

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Hippo signaling: A stress response pathway in stem cells

Current Stem Cell Research & Therapy ◽

10.2174/1574888x16666210712100002 ◽

2021 ◽

Vol 16 ◽

Author(s):

Naciye Dilara Zeybek ◽

Eylem Baysal ◽

Ozlem Bozdemir ◽

Esra Buber

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Stem Cell ◽

Stress Response ◽

Biological Effects ◽

Energy Levels ◽

Hippo Pathway ◽

Hippo Signaling ◽

Stress Response Pathway ◽

The Hippo Pathway

: The Hippo pathway, with its core components and the downstream transcriptional coactivators, controls the self-renewable capacity and stemness features of stem cells and serves as a stress response pathway by regulating proliferation, differentiation, and apoptosis. The Hippo pathway interaction with other signaling ways plays a vital role in response to various stress stimuli arising from energy metabolism, hypoxia, reactive oxygen species, and mechanical forces. Depending on the energy levels, the Hippo pathway is regulated by AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR), which in turn determines stem cell proliferation (cell survival and growth) and differentiation. Oxidative stress-driven by ROS production also affects the Hippo pathway with transcriptional changes through MST/YAP/FoxO pathway and leads to the activation of pro-apoptotic genes and eventually cell death. HIF1alpha/YAP signaling is critical for the long-term maintenance of mesenchymal stem cells (MSCs) under hypoxia. In this review, we present an overview of stem cell response to stress, including mechanical, hypoxia, metabolic and oxidative stress through the modulation of the Hippo pathway. The biological effects such as autophagy, apoptosis and senescence were discussed in the context of the Hippo pathway in stem cells.

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Lola regulates Drosophila adult midgut homeostasis via non-canonical hippo signaling

eLife ◽

10.7554/elife.47542 ◽

2020 ◽

Vol 9 ◽

Author(s):

Xue Hao ◽

Shimin Wang ◽

Yi Lu ◽

Wentao Yu ◽

Pengyue Li ◽

...

Keyword(s):

Transcription Factor ◽

Stem Cell ◽

Hippo Pathway ◽

Tissue Homeostasis ◽

Intestinal Stem Cell ◽

Hippo Signaling ◽

Intestinal Function ◽

Independent Manner ◽

The Hippo Pathway ◽

Basal Proliferation

Tissue homeostasis and regeneration in the Drosophila midgut is regulated by a diverse array of signaling pathways including the Hippo pathway. Hippo signaling restricts intestinal stem cell (ISC) proliferation by sequestering the transcription co-factor Yorkie (Yki) in the cytoplasm, a factor required for rapid ISC proliferation under injury-induced regeneration. Nonetheless, the mechanism of Hippo-mediated midgut homeostasis and whether canonical Hippo signaling is involved in ISC basal proliferation are less characterized. Here we identify Lola as a transcription factor acting downstream of Hippo signaling to restrict ISC proliferation in a Yki-independent manner. Not only that Lola interacts with and is stabilized by the Hippo signaling core kinase Warts (Wts), Lola rescues the enhanced ISC proliferation upon Wts depletion via suppressing Dref and SkpA expressions. Our findings reveal that Lola is a non-canonical Hippo signaling component in regulating midgut homeostasis, providing insights on the mechanism of tissue maintenance and intestinal function.

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Increasing kinase domain proximity promotes MST2 autophosphorylation during Hippo signaling

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015723 ◽

2020 ◽

Vol 295 (47) ◽

pp. 16166-16179

Author(s):

Thao Tran ◽

Jaba Mitra ◽

Taekjip Ha ◽

Jennifer M. Kavran

Keyword(s):

Single Molecule ◽

Hippo Pathway ◽

Signal Propagation ◽

Kinase Domain ◽

Specific Protein ◽

Hippo Signaling ◽

Membrane Recruitment ◽

Chemically Induced Dimerization ◽

The Hippo Pathway

The Hippo pathway plays an important role in developmental biology, mediating organ size by controlling cell proliferation through the activity of a core kinase cassette. Multiple upstream events activate the pathway, but how each controls this core kinase cassette is not fully understood. Activation of the core kinase cassette begins with phosphorylation of the kinase MST1/2 (also known as STK3/4). Here, using a combination of in vitro biochemistry and cell-based assays, including chemically induced dimerization and single-molecule pulldown, we revealed that increasing the proximity of adjacent kinase domains, rather than formation of a specific protein assembly, is sufficient to trigger autophosphorylation. We validate this mechanism in cells and demonstrate that multiple events associated with the active pathway, including SARAH domain–mediated homodimerization, membrane recruitment, and complex formation with the effector protein SAV1, each increase the kinase domain proximity and autophosphorylation of MST2. Together, our results reveal that multiple and distinct upstream signals each utilize the same common molecular mechanism to stimulate MST2 autophosphorylation. This mechanism is likely conserved among MST2 homologs. Our work also highlights potential differences in Hippo signal propagation between each activating event owing to differences in the dynamics and regulation of each protein ensemble that triggers MST2 autophosphorylation and possible redundancy in activation.

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NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway

The Journal of Cell Biology ◽

10.1083/jcb.201009069 ◽

2011 ◽

Vol 193 (4) ◽

pp. 633-642 ◽

Cited By ~ 89

Author(s):

Sandra Habbig ◽

Malte P. Bartram ◽

Roman U. Müller ◽

Ricarda Schwarz ◽

Nikolaos Andriopoulos ◽

...

Keyword(s):

Cell Proliferation ◽

Cellular Proliferation ◽

Nuclear Translocation ◽

Hippo Pathway ◽

Negative Regulator ◽

Hippo Signaling ◽

Transcriptional Coactivator ◽

Hippo Signaling Pathway ◽

The Hippo Pathway ◽

Potent Negative Regulator

The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.

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The Hippo Pathway: A Master Regulatory Network Important in Cancer

Cells ◽

10.3390/cells10061416 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1416

Author(s):

Qiuping Liu ◽

Xiaomeng Liu ◽

Guanbin Song

Keyword(s):

Metabolic Regulation ◽

Human Cancer ◽

Hippo Pathway ◽

Tumor Development ◽

Biological Significance ◽

Cancer Development ◽

Hippo Signaling ◽

Complex Regulation ◽

And Function ◽

The Hippo Pathway

The Hippo pathway is pervasively activated and has been well recognized to play critical roles in human cancer. The deregulation of Hippo signaling involved in cancer development, progression, and resistance to cancer treatment have been confirmed in several human cancers. Its biological significance and deregulation in cancer have drawn increasing interest in the past few years. A fundamental understanding of the complexity of the Hippo pathway in cancer is crucial for improving future clinical interventions and therapy for cancers. In this review, we try to clarify the complex regulation and function of the Hippo signaling network in cancer development, including its role in signal transduction, metabolic regulation, and tumor development, as well as tumor therapies targeting the Hippo pathway.

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Shavenbaby and Yorkie mediate Hippo signaling to protect adult stem cells from apoptosis

Nature Communications ◽

10.1038/s41467-018-07569-0 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 9

Author(s):

Jérôme Bohère ◽

Alexandra Mancheno-Ferris ◽

Sandy Al Hayek ◽

Jennifer Zanet ◽

Philippe Valenti ◽

...

Keyword(s):

Stem Cells ◽

Adult Stem Cells ◽

Hippo Signaling

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The Hippo Pathway: Immunity and Cancer

Cancers ◽

10.3390/cancers10040094 ◽

2018 ◽

Vol 10 (4) ◽

pp. 94 ◽

Cited By ~ 38

Author(s):

Zaid Taha ◽

Helena Janse van Rensburg ◽

Xiaolong Yang

Keyword(s):

Immune Response ◽

Immune Cells ◽

Mammalian Cells ◽

Immune Cell ◽

Hippo Pathway ◽

Tissue Homeostasis ◽

Hippo Signaling ◽

Core Components ◽

The Hippo Pathway ◽

Future Work

Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway has been implicated in multiple pathologies, including cancer. Recent studies have uncovered new roles for the Hippo pathway in immunology. In this review, we summarize the mechanisms by which Hippo signaling in pathogen-infected or neoplastic cells affects the activities of immune cells that respond to these threats. We further discuss how Hippo signaling functions as part of an immune response. Finally, we review how immune cell-intrinsic Hippo signaling modulates the development/function of leukocytes and propose directions for future work.

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Drosophila Hcf regulates the Hippo signaling pathway via association with the histone H3K4 methyltransferase Trr

Biochemical Journal ◽

10.1042/bcj20180717 ◽

2019 ◽

Vol 476 (4) ◽

pp. 759-768 ◽

Cited By ~ 5

Author(s):

Zi Nan ◽

Weiwei Yang ◽

Jialan Lyu ◽

Fang Wang ◽

Qiannan Deng ◽

...

Keyword(s):

Host Cell ◽

Signaling Pathway ◽

Hippo Pathway ◽

Organ Size ◽

Fundamental Aspect ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Host Cell Factor ◽

Histone H3k4 ◽

The Hippo Pathway

Abstract Control of organ size is a fundamental aspect in biology and plays important roles in development. The Hippo pathway is a conserved signaling cascade that controls tissue and organ size through the regulation of cell proliferation and apoptosis. Here, we report on the roles of Hcf (host cell factor), the Drosophila homolog of Host cell factor 1, in regulating the Hippo signaling pathway. Loss-of-Hcf function causes tissue undergrowth and the down-regulation of Hippo target gene expression. Genetic analysis reveals that Hcf is required for Hippo pathway-mediated overgrowth. Mechanistically, we show that Hcf associates with the histone H3 lysine-4 methyltransferase Trithorax-related (Trr) to maintain H3K4 mono- and trimethylation. Thus, we conclude that Hcf positively regulates Hippo pathway activity through forming a complex with Trr and controlling H3K4 methylation.

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A83 INTESTINAL EPITHELIAL CELL STEMNESS AND DIFFERENTIATION ARE REGULATED BY THE HIPPO PATHWAY EFFECTOR YAP1

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwz047.082 ◽

2020 ◽

Vol 3 (Supplement_1) ◽

pp. 97-98

Author(s):

S Fallah ◽

J Beaulieu

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Transcription Factors ◽

Cancer Stem Cells ◽

Hippo Pathway ◽

High Rate ◽

Intestinal Cell ◽

Intestinal Differentiation ◽

Ht29 Cells ◽

The Hippo Pathway

Abstract Background The high rate of cell turnover in the intestinal epithelium is supported by the LGR5+ crypt base columnar (CBC) stem cells, which are located at the lower part of the gland. Among of the various factors and signals like Wnt and Notch, YAP1 (yes associated protein) also plays an important role in stemness of CBC stem cells. YAP1 is the effector of the Hippo pathway. Hippo Pathway restricts the cells proliferation, tissues overgrowth and cancer formation through the phosphorylation and inactivation of the YAP1 protein. When active, YAP1 transfers into nucleus, forms the complex with TEADs transcription factors and promotes the transcription of genes involved in cell growth and proliferation. Aims In the present study, we investigated the role of the YAP1 in the colorectal cancer multipotent HT29 cell line, which contain cancer stem cells (CSC). Methods For approaching to this goal, YAP1 expression was knocked down using shRNAs in HT29 cells. Then stem cells and intestinal cell lineages (secretory goblet, Paneth and enteroendocrine and absorptive) markers expression was analyzed using qPCR and Western blot. Results The results showed the reduction of the expression of stem cells markers including LGR5 in YAP1 knockdown HT29 cells compare with control. Expression of the goblet cells markers (MUC2 and trefoil factor 3) and absorptive cells markers (sucrase-isomaltase and dipeptidylpeptidase IV) were significantly increased in YAP1 knockdown cells but Paneth (DEFA5 and lysozyme) and enteroendocrine (CHGA) were not detected. Finally, examination of the main transcription factors for intestinal differentiation revealed an increase in CDX2 expression. Conclusions These results suggest that YAP1 is involved in the maintenance of colorectal cancer stem cells while preventing intestinal differentiation in both secretory and absorptive lineages through the repression of CDX2. Funding Agencies CIHR

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