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| Open AccessCancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens
YAP activation is a key driver in both malignant pleural mesothelioma and uveal melanoma through engagement of different regulatory elements. Here, the authors use functional epigenomic analyses to reveal lineage-specific YAP-dependent cistrome.
- Inês A. M. Barbosa
- , Rajaraman Gopalakrishnan
- & Giorgio G. Galli
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Article
| Open AccessThe Hippo pathway links adipocyte plasticity to adipose tissue fibrosis
Adipose tissue fibrosis is connected to obesity-related metabolic dysfunction. Qiu and colleagues discover that the Hippo pathway acts as a molecular switch in the initiation and development of adipose tissue fibrosis upon TGFβ stimulation.
- Hongyu Shen
- , Xun Huang
- & Yifu Qiu
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Article
| Open AccessYAP inhibits ERα and ER+ breast cancer growth by disrupting a TEAD-ERα signaling axis
Recent studies have reported that oncoprotein YAP can function as tumour suppressor in certain contexts. Here the authors show that inhibition of Hippo signalling or YAP activation blocks ERα transcriptional program and ER + breast cancer growth and mechanistically this is through YAP interfering with TEAD-ERα signalling axis.
- Xu Li
- , Shu Zhuo
- & Jin Jiang
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| Open AccessProteogenomic characterization of 2002 human cancers reveals pan-cancer molecular subtypes and associated pathways
Pan-cancer proteomics analysis enables the analysis of protein expression across multiple cancer types. Here, the authors compare proteomics from 14 cancer types and show 11 distinct subtypes across multiple cancer types. Proteome data could link higher pathway activity levels with somatic alteration of specific genes in the pathway.
- Yiqun Zhang
- , Fengju Chen
- & Chad J. Creighton
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| Open AccessTranscriptional repression of estrogen receptor alpha by YAP reveals the Hippo pathway as therapeutic target for ER+ breast cancer
Hippo signalling is reported to be required for proper ESR1 expression. Here the authors reveal that the transcriptional repression of ESR1 is via LATS-YAP-TEAD-VGLL3 axis and the epigenetic regulation of ESR1 super enhancer in ER + breast cancer.
- Shenghong Ma
- , Tracy Tang
- & Kun-Liang Guan
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| Open AccessCell adhesion molecule KIRREL1 is a feedback regulator of Hippo signaling recruiting SAV1 to cell-cell contact sites
How cell-cell contact is sensed by Hippo pathway is poorly understood. Here, the authors show that KIRREL1 functions as a feedback regulator of the mammalian Hippo pathway by sensing cell-cell interaction and recruiting SAV1 to cell-cell contacts.
- Atanu Paul
- , Stefano Annunziato
- & Feng Cong
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Article
| Open AccessA protein tertiary structure mimetic modulator of the Hippo signalling pathway
Targeting the interaction between transcription factor TEAD and its co-repressor VGL4 is an attractive strategy to chemically modulate Hippo signaling. Here, the authors develop a proteomimetic with stabilized tertiary structure that inhibits the TEAD:VGL4 interaction in vitro and in cells.
- Hélène Adihou
- , Ranganath Gopalakrishnan
- & Herbert Waldmann
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| Open AccessMechano-modulatory synthetic niches for liver organoid derivation
3D liver organoids hold great promise for regenerative medicine but the use of ill-defined matrices limits their potential. Here, the authors generate human and mouse liver organoids using a chemically defined matrix, and reveal a link between matrix stiffness and organoid growth that does not require acto-myosin contraction.
- Giovanni Sorrentino
- , Saba Rezakhani
- & Kristina Schoonjans
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| Open AccessYAP1/TAZ-TEAD transcriptional networks maintain skin homeostasis by regulating cell proliferation and limiting KLF4 activity
Hippo TEAD-transcriptional regulators YAP1 and TAZ modulate cell growth, but the downstream networks are unclear. Here, the authors use a genetically-encoded inhibitor of YAP1/TAZ interaction with TEAD (TEADi) to disrupt transcriptional networks for cell cycle and terminal differentiation in human keratinocytes and mouse skin.
- Yao Yuan
- , Jeannie Park
- & Ramiro Iglesias-Bartolome
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| Open AccessIdentification of the kinase STK25 as an upstream activator of LATS signaling
Hippo pathway inactivation plays a role in many cancers, although how tumor cells depress signaling is unclear. Here, Lim et al. identify STK25, which activates LATS in a manner distinct from other upstream kinases and is focally deleted from a range of human cancers.
- Sanghee Lim
- , Nicole Hermance
- & Neil J. Ganem
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| Open AccessUsp7 regulates Hippo pathway through deubiquitinating the transcriptional coactivator Yorkie
Hippo signaling leads to the phosphorylation of the key transcriptional effector, Yap/Yki, although how Yap/Yki stability is regulated has remained unclear. Here, Sun et al. identify HAUSP/Usp7 as a conserved and clinically relevant regulator of the Hippo pathway that increases Yap/Yki stability.
- Xiaohan Sun
- , Yan Ding
- & Zizhang Zhou
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Article
| Open AccessAutophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap
Increased levels of the Yap oncoprotein stimulate liver growth and promote hepatocarcinogenesis. Here the authors show that hepatocyte-specific loss of Atg7 in mice leads to decreased autophagic degradation of Yap and liver overgrowth, and further establish this association in human liver cancer tissues.
- Youngmin A. Lee
- , Luke A. Noon
- & Scott L. Friedman
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| Open AccessMediated nuclear import and export of TAZ and the underlying molecular requirements
The transcriptional co-factors Yap and TAZ are regulated by Hippo signalling and mechanical forces via their nucleocytoplasmic shuttling. Here the authors identify a RhoA-regulated C-terminal nuclear localization signal and a TEAD-regulated N-terminal nuclear export signal of TAZ in an epithelial cell line.
- Michael Kofler
- , Pam Speight
- & András Kapus
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Article
| Open AccessNUAK2 is a critical YAP target in liver cancer
Hippo-YAP pathway plays an important role in cancers; however the in vivo relevance of YAP/TAZ target genes is unclear. Here, the authors show that NUAK2 is a target of YAP and participates in a feedback loop to maximize YAP activity. Inhibition of NUAK2 suppresses YAP-driven hepatomegaly and liver cancer growth, offering a new target for cancer therapy.
- Wei-Chien Yuan
- , Brian Pepe-Mooney
- & Fernando D. Camargo
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| Open AccessA LATS biosensor screen identifies VEGFR as a regulator of the Hippo pathway in angiogenesis
The Hippo pathway is a major orchestrator of organ development and homeostasis. Here Azad and colleagues develop a biosensor to monitor the activity of the Hippo pathway component LATS and identify VEGF signalling as an upstream regulator of LATS, supporting a role for Hippo signalling during angiogenesis.
- T. Azad
- , H. J. Janse van Rensburg
- & X. Yang
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| Open AccessEndosomal phosphatidylserine is critical for the YAP signalling pathway in proliferating cells
Yes-associated protein (YAP) is a growth-promoting transcription co-activator that regulates the malignancy of various cancers, however its regulation is not fully understood. Here the authors show that phosphatdylserine at recycling endosomes regulates YAP signalling pathway.
- Tatsuyuki Matsudaira
- , Kojiro Mukai
- & Tomohiko Taguchi
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| Open AccessA genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells
Individual human epidermal cells differ in their self-renewal ability. Here the authors perform genome-wide pooled RNAi screens to uncover the molecular basis for this heterogeneity, and identify genes conferring a clonal growth advantage on normal and neoplastic human epidermal cells.
- Gernot Walko
- , Samuel Woodhouse
- & Fiona M. Watt
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| Open AccessOptimal myelin elongation relies on YAP activation by axonal growth and inhibition by Crb3/Hippo pathway
Molecular mechanisms regulating optimal myelin geometry are only partially understood. Here authors show that peripheral myelin growth is orchestrated by the Crb3/Hippo/YAP pathway, and that defects in YAP activation may underlie peripheral neuropathies caused by shorter myelin.
- Ruani N. Fernando
- , Laurent Cotter
- & Nicolas Tricaud
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| Open AccessA splicing isoform of TEAD4 attenuates the Hippo–YAP signalling to inhibit tumour proliferation
The Hippo/Yap signalling pathway is found deregulated in several cancers. Here, the authors uncover an additional mechanism of YAP regulation that occurs via alternately spliced isoform of TEAD4, which acts as a dominant negative regulator of YAP-TEAD signalling.
- Yangfan Qi
- , Jing Yu
- & Zefeng Wang
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| Open AccessThe Hippo signalling pathway maintains quiescence in Drosophila neural stem cells
Drosophila neural stem cells (NSCs) are quiescent at early larval stages but how this is regulated is unclear. Here, Ding et al. show that quiescence of NSCs is mediated by cell-contact inhibition via the Hippo pathway transmembrane proteins Crumbs and Echinoid, which in turn are regulated by nutrient levels.
- Rouven Ding
- , Kevin Weynans
- & Christian Berger
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| Open AccessMAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway
A variety of signals have been reported to either activate or inhibit the Hippo kinase cascade. Here, Meng et al. show that mitogen activated protein kinase kinase kinase kinase (MAP4K) family members function in parallel to and are partially redundant with MST1/2 in regulating LATS in response to upstream signals.
- Zhipeng Meng
- , Toshiro Moroishi
- & Kun-Liang Guan
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| Open AccessLocalization of Hippo signalling complexes and Warts activation in vivo
Components of the Hippo signalling pathway localize to apical junctions in epithelial cells, where they regulate growth in response to mechanical and biochemical cues. Sun et al. show that these proteins are organized into distinct junctional complexes, which reorganize up on Hippo pathway activation.
- Shuguo Sun
- , B. V. V. G. Reddy
- & Kenneth D. Irvine
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Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2
Angiogenesis is regulated by dynamic changes in endothelial cell contact. Here, the authors show that signals from endothelial cell junctions affect the subcellular localization and function of Yes-associated protein, ultimately modifying angiopoietin-2 expression and angiogenic activity of endothelial cells.
- Hyun-Jung Choi
- , Haiying Zhang
- & Young-Guen Kwon
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Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells
Transcriptional regulators Sox2 and YAP maintain expression of stemness genes in normal and cancerous cells. Here the authors show that, in osteosarcomas, Sox2 activates YAP by directly repressing transcription of its upstream negative regulators Nf2 and WWC1, promoting cancer cell stemness.
- Upal Basu-Roy
- , N. Sumru Bayin
- & Claudio Basilico
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Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis
The Hippo pathway is a major regulator of organ size and growth control. Here Wu et al. provide evidence for a novel link between the Hippo signalling pathway and the unfolded protein response (UPR) in regulating organ growth and tumorigenesis.
- Hongtan Wu
- , Luyao Wei
- & Dawang Zhou
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NEDD4 controls intestinal stem cell homeostasis by regulating the Hippo signalling pathway
The Hippo pathway plays a role in regulating organ size and stem cell renewal but the regulatory mechanisms that fine-tune this pathway are not well understood. Here the authors report on the role of NEDD4 as a negative regulator of the Hippo signalling components, WW45 and LATS kinase, and in controlling cell proliferation and intestinal stem cell homeostasis.
- Sung Jun Bae
- , Myungjin Kim
- & Jae Hong Seol
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The Hippo pathway effector YAP is a critical regulator of skeletal muscle fibre size
The Yes-associated protein (YAP) is a core effector of the Hippo pathway, which regulates proliferation and apoptosis in organ development, but its function in adult skeletal muscle remains poorly defined. Here the authors show that YAP is an essential regulator of myofibre size in adult skeletal muscle, via interaction with TEAD transcription factors.
- K. I. Watt
- , B. J. Turner
- & P. Gregorevic
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The MST1/2-SAV1 complex of the Hippo pathway promotes ciliogenesis
Although much is known about the structural and trafficking molecules involved in generation of primary cilia, the signalling proteins that regulate ciliogenesis are poorly defined. Here, Kim et al. identify the MST1/2-SAV1 complex, a core component of the Hippo pathway, as a key regulator of ciliogenesis in cells and zebrafish.
- Miju Kim
- , Minchul Kim
- & Dae-Sik Lim
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A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response
YAP is the terminal effector of the Hippo signalling pathway that regulates cell growth and survival. Shao et al.show that Hippo signalling also stimulates oxidative stress responses in cardiomyocytes, revealing YAP as a regulator of FoxO1-dependent antioxidant gene expression.
- Dan Shao
- , Peiyong Zhai
- & Junichi Sadoshima
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| Open AccessAngiomotin prevents pluripotent lineage differentiation in mouse embryos via Hippo pathway-dependent and -independent mechanisms
Angiomotins retain the transcription co-activator YAP in the cytoplasm and thereby regulate the Hippo pathway in mammalian cultured cells. Here Leung and Zernicka-Goetz show that Angiomotin family members prevent the differentiation of inner cell mass cells in the mouse blastocyst, via both Hippo pathway-dependent and -independent mechanisms.
- Chuen Yan Leung
- & Magdalena Zernicka-Goetz
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| Open AccessProteolysis of MOB1 by the ubiquitin ligase praja2 attenuates Hippo signalling and supports glioblastoma growth
Tumour suppressors can be inactivated in cancer not only as a result of mutation, but also by proteolytic degradation. Here the authors show that, during glioma development, the accumulation of the ubiquitin ligase praja2 sustains tumour growth by degrading MOB1—a core component of the Hippo pathway.
- Luca Lignitto
- , Antonietta Arcella
- & Antonio Feliciello