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

eLife ◽  
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.

scholarly journals The Hippo Pathway: Immunity and Cancer

Cancers ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 94 ◽  
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.

scholarly journals A Drosophila model of oral peptide therapeutics for adult intestinal stem cell tumors

2020 ◽  
Vol 13 (7) ◽  
pp. dmm044420 ◽  
Author(s):  
Anjali Bajpai ◽  
Taushif Ahmad Quazi ◽  
Hong-Wen Tang ◽  
Nishat Manzar ◽  
Virender Singh ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hippo Pathway ◽  
Intestinal Stem Cell ◽  
Peptide Therapeutics ◽  
Small Molecule Drugs ◽  
Drosophila Model ◽  
Therapeutic Peptides ◽  
Oral Therapeutic ◽  
The Hippo Pathway

ABSTRACTPeptide therapeutics, unlike small-molecule drugs, display crucial advantages of target specificity and the ability to block large interacting interfaces, such as those of transcription factors. The transcription co-factor of the Hippo pathway, YAP/Yorkie (Yki), has been implicated in many cancers, and is dependent on its interaction with the DNA-binding TEAD/Sd proteins via a large Ω-loop. In addition, the mammalian vestigial-like (VGLL) proteins, specifically their TONDU domain, competitively inhibit YAP-TEAD interaction, resulting in arrest of tumor growth. Here, we show that overexpression of the TONDU peptide or its oral uptake leads to suppression of Yki-driven intestinal stem cell tumors in the adult Drosophila midgut. In addition, comparative proteomic analyses of peptide-treated and untreated tumors, together with chromatin immunoprecipitation analysis, reveal that integrin pathway members are part of the Yki-oncogenic network. Collectively, our findings establish Drosophila as a reliable in vivo platform to screen for cancer oral therapeutic peptides and reveal a tumor suppressive role for integrins in Yki-driven tumors.This article has an associated First Person interview with the first author of the paper.

scholarly journals The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration

Development ◽  
2010 ◽  
Vol 137 (24) ◽  
pp. 4147-4158 ◽  
Author(s):  
R. L. Shaw ◽  
A. Kohlmaier ◽  
C. Polesello ◽  
C. Veelken ◽  
B. A. Edgar ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Stem Cell ◽  
Hippo Pathway ◽  
Intestinal Stem Cell ◽  
Stem Cell Proliferation ◽  
The Hippo Pathway

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

2017 ◽  
Author(s):  
Jérôme Bohère ◽  
Alexandra Mancheno-Ferris ◽  
Kohsuke Akino ◽  
Yuya Yamabe ◽  
Sachi Inagaki ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Transcription Factor ◽  
Adult Stem Cells ◽  
Hippo Pathway ◽  
Inhibitor Of Apoptosis ◽  
Hippo Signaling ◽  
Polished Rice ◽  
Organ Regeneration ◽  
The Hippo Pathway

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.

scholarly journals Mutations and Copy Number Abnormalities of Hippo Pathway Components in Human Cancers

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhengjin He ◽  
Ruihan Li ◽  
Hai Jiang
Keyword(s):  
Cell Proliferation ◽  
Cancer Cells ◽  
Copy Number ◽  
Human Cancer ◽  
Hippo Pathway ◽  
Copy Number Variations ◽  
Tissue Homeostasis ◽  
Hippo Signaling ◽  
Core Components ◽  
The Hippo Pathway

The Hippo pathway is highly conserved from Drosophila to mammals. As a key regulator of cell proliferation, the Hippo pathway controls tissue homeostasis and has a major impact on tumorigenesis. The originally defined core components of the Hippo pathway in mammals include STK3/4, LATS1/2, YAP1/TAZ, TEAD, VGLL4, and NF2. However, for most of these genes, mutations and copy number variations are relatively uncommon in human cancer. Several other recently identified upstream and downstream regulators of Hippo signaling, including FAT1, SHANK2, Gq/11, and SWI/SNF complex, are more commonly dysregulated in human cancer at the genomic level. This review will discuss major genomic events in human cancer that enable cancer cells to escape the tumor-suppressive effects of Hippo signaling.

Hippo signaling: A stress response pathway in stem cells

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.

scholarly journals The role of translationally controlled tumor protein in proliferation ofDrosophilaintestinal stem cells

2019 ◽  
Vol 116 (52) ◽  
pp. 26591-26598 ◽  
Author(s):  
Young V. Kwon ◽  
Bingqing Zhao ◽  
Chiwei Xu ◽  
Jiae Lee ◽  
Chiao-Lin Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Signaling Pathways ◽  
Hippo Pathway ◽  
Tissue Homeostasis ◽  
Translationally Controlled Tumor Protein ◽  
Cellular Processes ◽  
The Hippo Pathway

Translationally controlled tumor protein (TCTP) is a highly conserved protein functioning in multiple cellular processes, ranging from growth to immune responses. To explore the role of TCTP in tissue maintenance and regeneration, we employed the adultDrosophilamidgut, where multiple signaling pathways interact to precisely regulate stem cell division for tissue homeostasis. Tctp levels were significantly increased in stem cells and enteroblasts upon tissue damage or activation of the Hippo pathway that promotes regeneration of intestinal epithelium. Stem cells with reduced Tctp levels failed to proliferate during normal tissue homeostasis and regeneration. Mechanistically, Tctp forms a complex with multiple proteins involved in translation and genetically interacts with ribosomal subunits. In addition, Tctp increases both Akt1 protein abundance and phosphorylation in vivo. Altogether, Tctp regulates stem cell proliferation by interacting with key growth regulatory signaling pathways and the translation process in vivo.

scholarly journals STK25 suppresses Hippo signaling by regulating SAV1-STRIPAK antagonism

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Sung Jun Bae ◽  
Lisheng Ni ◽  
Xuelian Luo
Keyword(s):  
Hippo Pathway ◽  
Human Cells ◽  
Tissue Homeostasis ◽  
Organ Size ◽  
Scaffolding Protein ◽  
Hippo Signaling ◽  
Mutual Antagonism ◽  
Kinase Cascade ◽  
The Hippo Pathway

The MST-LATS kinase cascade is central to the Hippo pathway that controls tissue homeostasis, development, and organ size. The PP2A complex STRIPAKSLMAP blocks MST1/2 activation. The GCKIII family kinases associate with STRIPAK, but the functions of these phosphatase-associated kinases remain elusive. We previously showed that the scaffolding protein SAV1 promotes Hippo signaling by counteracting STRIPAK (Bae et al., 2017). Here, we show that the GCKIII kinase STK25 promotes STRIPAK-mediated inhibition of MST2 in human cells. Depletion of STK25 enhances MST2 activation without affecting the integrity of STRIPAKSLMAP. STK25 directly phosphorylates SAV1 and diminishes the ability of SAV1 to inhibit STRIPAK. Thus, STK25 as the kinase component of STRIPAK can inhibit the function of the STRIPAK inhibitor SAV1. This mutual antagonism between STRIPAK and SAV1 controls the initiation of Hippo signaling.

The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration

2010 ◽  
Vol 123 (24) ◽  
pp. e1-e1 ◽  
Author(s):  
R. L. Shaw ◽  
A. Kohlmaier ◽  
C. Polesello ◽  
C. Veelken ◽  
B. A. Edgar ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Stem Cell ◽  
Hippo Pathway ◽  
Intestinal Stem Cell ◽  
Stem Cell Proliferation ◽  
The Hippo Pathway

scholarly journals Increasing kinase domain proximity promotes MST2 autophosphorylation during Hippo signaling

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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