Genome editing of Capsaspora owczarzaki suggests an ancestral function of the Hippo signaling effector YAP/TAZ/Yorkie in cytoskeletal dynamics but not proliferation

Many genes that function in animal development are present in the close unicellular relatives of animals, but little is known regarding the premetazoan function of these genes. Here, we develop techniques for genetic manipulation in the filasterean Capsaspora owczarzaki and use these tools to characterize the Capsaspora ortholog of the Hippo signaling nuclear effector YAP/TAZ/Yorkie (coYki). In contrast to its potent oncogene activity in metazoans, we show that coYki is dispensable for cell proliferation but regulates cytoskeletal dynamics and the morphology of multicellular aggregates in Capsaspora. Our results suggest an ancestral role for the Hippo pathway in cytoskeletal regulation, which was later co-opted to regulate cell proliferation in animals.

Download Full-text

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.

Download Full-text

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

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.661718 ◽

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.

Download Full-text

YAP regulates cell proliferation, migration, and steroidogenesis in adult granulosa cell tumors

Endocrine Related Cancer ◽

10.1530/erc-13-0339 ◽

2014 ◽

Vol 21 (2) ◽

pp. 297-310 ◽

Cited By ~ 51

Author(s):

David Fu ◽

Xiangmin Lv ◽

Guohua Hua ◽

Chunbo He ◽

Jixin Dong ◽

...

Keyword(s):

Cell Proliferation ◽

Granulosa Cell ◽

Hippo Pathway ◽

Central Component ◽

Hippo Signaling ◽

Granulosa Cell Tumors ◽

Ovarian Granulosa Cell ◽

Estrogen Production ◽

And Migration ◽

The Hippo Pathway

The Hippo signaling pathway has been implicated as a conserved regulator of organ size in both Drosophila and mammals. Yes-associated protein (YAP), the central component of the Hippo signaling cascade, functions as an oncogene in several malignancies. Ovarian granulosa cell tumors (GCT) are characterized by enlargement of the ovary, excess production of estrogen, a high frequency of recurrence, and the potential for malignancy and metastasis. Whether the Hippo pathway plays a role in the pathogenesis of GCT is unknown. This study was conducted to examine the expression of YAP in human adult GCTs and to determine the role of YAP in the proliferation and steroidogenesis of GCT cells. Compared with age-matched normal human ovaries, GCT tissues exhibited higher levels of YAP expression. YAP protein was predominantly expressed in the nucleus of tumor cells, whereas the non-tumor ovarian stromal cells expressed very low levels of YAP. YAP was also expressed in cultured primary human granulosa cells and in KGN and COV434 GCT cell lines. siRNA-mediated knockdown of YAP in KGN cells resulted in a significant reduction in cell proliferation (P<0.001). Conversely, overexpression of wild type YAP or a constitutively active YAP (YAP1) mutant resulted in a significant increase in KGN cell proliferation and migration. Moreover, YAP knockdown reduced FSH-induced aromatase (CYP19A1) protein expression and estrogen production in KGN cells. These results demonstrate that YAP plays an important role in the regulation of GCT cell proliferation, migration, and steroidogenesis. Targeting the Hippo/YAP pathway may provide a novel therapeutic approach for GCT.

Download Full-text

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

Life Science Alliance ◽

10.26508/lsa.201900381 ◽

2019 ◽

Vol 2 (4) ◽

pp. e201900381 ◽

Cited By ~ 5

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.

Download Full-text

Faculty Opinions recommendation of The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1047296.497234 ◽

2006 ◽

Author(s):

Carl Thummel

Keyword(s):

Cell Proliferation ◽

Hippo Pathway ◽

Control Cell ◽

Proliferation And Apoptosis ◽

The Hippo Pathway

Download Full-text

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text