scholarly journals Deubiquitinating Enzyme USP9X Suppresses Tumor Growth via LATS Kinase and Core Components of the Hippo Pathway

2017 ◽  
Vol 77 (18) ◽  
pp. 4921-4933 ◽  
Author(s):  
Aleksandra Toloczko ◽  
Fusheng Guo ◽  
Hiu-Fung Yuen ◽  
Qing Wen ◽  
Stephen A. Wood ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Hippo Pathway ◽  
Deubiquitinating Enzyme ◽  
Core Components ◽  
The Hippo Pathway

scholarly journals Targeting the Hippo Pathway for Breast Cancer Therapy

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 422 ◽  
Author(s):  
Liqing Wu ◽  
Xiaolong Yang
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Targeted Therapies ◽  
Hippo Pathway ◽  
Targeted Drugs ◽  
Breast Cancer Therapy ◽  
The World ◽  
Core Components ◽  
Future Direction ◽  
The Hippo Pathway

Breast cancer (BC) is one of the most prominent diseases in the world, and the treatments for BC have many limitations, such as resistance and a lack of reliable biomarkers. Currently the Hippo pathway is emerging as a tumor suppressor pathway with its four core components that regulate downstream transcriptional targets. In this review, we introduce the present targeted therapies of BC, and then discuss the roles of the Hippo pathway in BC. Finally, we summarize the evidence of the small molecule inhibitors that target the Hippo pathway, and then discuss the possibilities and future direction of the Hippo-targeted drugs for BC therapy.

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 Tubule-Specific Mst1/2 Deficiency Induces CKD via YAP and Non-YAP Mechanisms

2020 ◽  
Vol 31 (5) ◽  
pp. 946-961 ◽  
Author(s):  
Chunhua Xu ◽  
Li Wang ◽  
Yu Zhang ◽  
Wenling Li ◽  
Jinhong Li ◽  
...  
Keyword(s):  
Kidney Development ◽  
Collecting Duct ◽  
Hippo Pathway ◽  
Binding Motif ◽  
Renal Tubules ◽  
Double Knockout ◽  
Core Components ◽  
Collecting Duct Cells ◽  
Medullary Collecting Duct ◽  
The Hippo Pathway

BackgroundThe serine/threonine kinases MST1 and MST2 are core components of the Hippo pathway, which has been found to be critically involved in embryonic kidney development. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the pathway’s main effectors. However, the biologic functions of the Hippo/YAP pathway in adult kidneys are not well understood, and the functional role of MST1 and MST2 in the kidney has not been studied.MethodsWe used immunohistochemistry to examine expression in mouse kidneys of MST1 and MST2, homologs of Hippo in Drosophila. We generated mice with tubule-specific double knockout of Mst1 and Mst2 or triple knockout of Mst1, Mst2, and Yap. PCR array and mouse inner medullary collecting duct cells were used to identify the primary target of Mst1/Mst2 deficiency.ResultsMST1 and MST2 were predominantly expressed in the tubular epithelial cells of adult kidneys. Deletion of Mst1/Mst2 in renal tubules increased activity of YAP but not TAZ. The kidneys of mutant mice showed progressive inflammation, tubular and glomerular damage, fibrosis, and functional impairment; these phenotypes were largely rescued by deletion of Yap in renal tubules. TNF-α expression was induced via both YAP-dependent and YAP-independent mechanisms, and TNF-α and YAP amplified the signaling activities of each other in the tubules of kidneys with double knockout of Mst1/Mst2.ConclusionsOur findings show that tubular Mst1/Mst2 deficiency leads to CKD through both the YAP and non-YAP pathways and that tubular YAP activation induces renal fibrosis. The pathogenesis seems to involve the reciprocal stimulation of TNF-α and YAP signaling activities.

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.

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 CDK7 regulates organ size and tumor growth by safeguarding the Hippo pathway effector Yki/Yap/Taz in the nucleus

2019 ◽  
Vol 34 (1-2) ◽  
pp. 53-71 ◽  
Author(s):  
Yong Suk Cho ◽  
Shuang Li ◽  
Xiaohui Wang ◽  
Jian Zhu ◽  
Shu Zhuo ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Hippo Pathway ◽  
Organ Size ◽  
The Hippo Pathway

scholarly journals O-GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity

2020 ◽  
pp. 201913469 ◽  
Author(s):  
Eunah Kim ◽  
Jeong Gu Kang ◽  
Min Jueng Kang ◽  
Jae Hyung Park ◽  
Yeon Jung Kim ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cancer Cells ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Hippo Pathway ◽  
Critical Role ◽  
Adaptor Protein ◽  
Negative Regulator ◽  
Negative Feedback Loop ◽  
The Hippo Pathway

The Hippo pathway controls organ size and tissue homeostasis by regulating cell proliferation and apoptosis. The LATS-mediated negative feedback loop prevents excessive activation of the effectors YAP/TAZ, maintaining homeostasis of the Hippo pathway. YAP and TAZ are hyperactivated in various cancer cells which lead to tumor growth. Aberrantly increased O-GlcNAcylation has recently emerged as a cause of hyperactivation of YAP in cancer cells. However, the mechanism, which induces hyperactivation of TAZ and blocks LATS-mediated negative feedback, remains to be elucidated in cancer cells. This study found that in breast cancer cells, abnormally increased O-GlcNAcylation hyperactivates YAP/TAZ and inhibits LATS2, a direct negative regulator of YAP/TAZ. LATS2 is one of the newly identified O-GlcNAcylated components in the MST-LATS kinase cascade. Here, we found that O-GlcNAcylation at LATS2 Thr436 interrupted its interaction with the MOB1 adaptor protein, which connects MST to LATS2, leading to activation of YAP/TAZ by suppressing LATS2 kinase activity. LATS2 is a core component in the LATS-mediated negative feedback loop. Thus, this study suggests that LATS2 O-GlcNAcylation is deeply involved in tumor growth by playing a critical role in dysregulation of the Hippo pathway in cancer cells.

scholarly journals Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability

2017 ◽  
Vol 114 (18) ◽  
pp. 4691-4696 ◽  
Author(s):  
Youngeun Kim ◽  
Wantae Kim ◽  
Yonghee Song ◽  
Jeong-Rae Kim ◽  
Kyungjoo Cho ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Dependent Manner ◽  
Subsequent Increase ◽  
Biological Responses ◽  
Expression Of Genes ◽  
Core Components ◽  
The Stability ◽  
The Hippo Pathway

Hippo signaling controls the expression of genes regulating cell proliferation and survival and organ size. The regulation of core components in the Hippo pathway by phosphorylation has been extensively investigated, but the roles of ubiquitination−deubiquitination processes are largely unknown. To identify deubiquitinase(s) that regulates Hippo signaling, we performed unbiased siRNA screening and found that YOD1 controls biological responses mediated by YAP/TAZ. Mechanistically, YOD1 deubiquitinates ITCH, an E3 ligase of LATS, and enhances the stability of ITCH, which leads to reduced levels of LATS and a subsequent increase in the YAP/TAZ level. Furthermore, we show that the miR-21-mediated regulation of YOD1 is responsible for the cell-density-dependent changes in YAP/TAZ levels. Using a transgenic mouse model, we demonstrate that the inducible expression of YOD1 enhances the proliferation of hepatocytes and leads to hepatomegaly in a YAP/TAZ-activity-dependent manner. Moreover, we find a strong correlation between YOD1 and YAP expression in liver cancer patients. Overall, our data strongly suggest that YOD1 is a regulator of the Hippo pathway and would be a therapeutic target to treat liver cancer.

scholarly journals CORO7 functions as a scaffold protein for the core kinase complex assembly of the Hippo pathway

2020 ◽  
pp. jbc.RA120.013297
Author(s):  
Jina Park ◽  
Kyoungho Jun ◽  
Yujin Choi ◽  
Eunju Yoon ◽  
Wonho Kim ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Cell Contact ◽  
Protein Protein Interactions ◽  
The Core ◽  
Core Components ◽  
Pathway Regulation ◽  
The Hippo Pathway

The Hippo pathway controls organ size and tissue homeostasis through the regulation of cell proliferation and apoptosis. However, the exact molecular mechanisms underpinning Hippo pathway regulation is not fully understood. Here, we identify a new component of the Hippo pathway: CORO7, a coronin protein family member that is involved in organization of the actin cytoskeleton. pod1, the Drosophila orthologue of CORO7, genetically interacts with key Hippo pathway genes in Drosophila. In mammalian cells, CORO7 is required for the activation of the Hippo pathway in response to cell-cell contact, serum deprivation, and cytoskeleton damage. CORO7 forms a complex with the core components of the pathway and functions as a scaffold for the Hippo core kinase complex. Collectively, these results demonstrate that CORO7 is a key scaffold controlling the Hippo pathway via modulating protein-protein interactions.

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