scholarly journals YAP regulates cell size and growth dynamics via non-cell autonomous mediators

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Douaa Mugahid ◽  
Marian Kalocsay ◽  
Xili Liu ◽  
Jonathan Scott Gruver ◽  
Leonid Peshkin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Size ◽  
Cultured Cells ◽  
Hippo Pathway ◽  
Growth Dynamics ◽  
Cell Number ◽  
Hek293 Cells ◽  
Tissue Size ◽  
The Stability ◽  
The Hippo Pathway

The Hippo pathway regulates organ size, regeneration, and cell growth by controlling the stability of the transcription factor, YAP (Yorkie in Drosophila). When there is tissue damage, YAP is activated allowing the restoration of homeostatic tissue size. The exact signals by which YAP is activated are still not fully understood, but its activation is known to affect both cell size and cell number. Here we used cultured cells to examine the coordinated regulation of cell size and number under the control of YAP. Our experiments in isogenic HEK293 cells reveal that YAP can affect cell size and number by independent circuits. Some of these effects are cell autonomous, such as proliferation, while others are mediated by secreted signals. In particular CYR61, a known secreted YAP target, is a non-cell autonomous mediator of cell survival, while another unidentified secreted factor controls cell size.

YAP independently regulates cell size and population growth dynamics via non-cell autonomous mediators

2018 ◽  
Author(s):  
Douaa Mugahid ◽  
Marian Kalocsay ◽  
Scott Gruver ◽  
Leonid Peshkin ◽  
Marc W. Kirschner
Keyword(s):  
Cell Size ◽  
Mammalian Cells ◽  
Hippo Pathway ◽  
Growth Dynamics ◽  
Cell Number ◽  
Tissue Growth ◽  
Environment Control ◽  
Important Pathway ◽  
The Hippo Pathway

SummaryThe Hippo pathway, in which changes at the cell surface and in the extracellular environment control the activity of a downstream transcription factor, known as YAP in mammalian cells and Yorkie in Drosophila, has recently taken center-stage as perhaps the most important pathway in metazoans for controlling organ size. In intact tissues YAP activity is inhibited and the organ does not overgrow. When the organ is damaged, YAP is active and necessary for growth and regeneration to occur. The exact process by which YAP drives organ and tissue growth is not fully understood, although it is known to affect both cell size and cell number. Since cell size and proliferation are highly interdependent in many cultured cell studies, we investigated the role of YAP in the simultaneous regulation of both cell size and number. Our experiments reveal that YAP controls both cell size and cell proliferation by independent circuits, and that it affects each process non-cell autonomously via extracellular mediators. We identify that CYR61, a known secreted YAP target, is the major regulator of the non-cell autonomous increase in cell number, but does not affect cell size. The molecular identity of the non-cell autonomously acting mediator of cell size is yet to be identified.

scholarly journals Transcription factor NRF2 uses the Hippo pathway effector TAZ to induce tumorigenesis in glioblastomas

Redox Biology ◽  
2020 ◽  
Vol 30 ◽  
pp. 101425 ◽  
Author(s):  
Maribel Escoll ◽  
Diego Lastra ◽  
Marta Pajares ◽  
Natalia Robledinos-Antón ◽  
Ana I. Rojo ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Hippo Pathway ◽  
The Hippo Pathway

DNA-binding mechanism of the Hippo pathway transcription factor TEAD4

Oncogene ◽  
2017 ◽  
Vol 36 (30) ◽  
pp. 4362-4369 ◽  
Author(s):  
Z Shi ◽  
F He ◽  
M Chen ◽  
L Hua ◽  
W Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Hippo Pathway ◽  
Binding Mechanism ◽  
The Hippo Pathway

scholarly journals The Hippo pathway effector Taz is required for cell fate specification and fertilization in zebrafish

2018 ◽  
Author(s):  
Chaitanya Dingare ◽  
Alina Niedzwetzki ◽  
Petra A Klemmt ◽  
Svenja Godbersen ◽  
Ricardo Fuentes ◽  
...  
Keyword(s):  
Cell Size ◽  
Cell Fate ◽  
Hippo Pathway ◽  
Follicle Cells ◽  
Cell Fate Specification ◽  
Critical Pathway ◽  
Animal Pole ◽  
Fate Specification ◽  
Shape Acquisition ◽  
The Hippo Pathway

SUMMARYIn the last decade, Hippo signaling has emerged as a critical pathway integrating extrinsic and intrinsic mechanical cues to regulate cell proliferation and survival, tissue morphology and organ size in vivo. Despite its essential role in organogenesis, surprisingly much less is known about how it connects biomechanical signals to control of cell fate and cell size during development. Here we unravel a novel and unexpected role of the Hippo pathway effector Taz (wwtr1) in the control of cell size and cell fate specification. In teleosts, fertilization occurs through a specific structure at the animal pole, called the micropyle. This opening in the chorion is formed during oogenesis by a specialized somatic follicle cell, the micropylar cell (MC). The MC has a peculiar shape and is much larger than its neighboring follicle cells but the mechanisms underlying its specification and cell shape acquisition are not known. Here we show that Taz is essential for the specification of the MC and subsequent micropyle formation in zebrafish. We identify Taz as the first bona fide MC marker and show that Taz is specifically and strongly enriched in the MC precursor before the cell can be identified morphologically. Altogether, our genetic data and molecular characterization of the MC lead us to propose that Taz is a key regulator of the MC fate activated by physical cues emanating from the oocyte to initiate the MC morphogenetic program. We describe here for the first time the mechanism underlying the specification of the MC fate.

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 Parallel Activin and BMP signaling coordinates R7/R8 photoreceptor subtype pairing in the stochastic Drosophila retina

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Brent S Wells ◽  
Daniela Pistillo ◽  
Erin Barnhart ◽  
Claude Desplan
Keyword(s):  
Transcription Factor ◽  
Color Vision ◽  
Growth Regulator ◽  
Hippo Pathway ◽  
Bmp Signaling ◽  
Processing Factor ◽  
Activin Receptor ◽  
The Hippo Pathway ◽  
To Receive ◽  
Tgfβ Pathway

Drosophila color vision is achieved by comparing outputs from two types of color-sensitive photoreceptors, R7 and R8. Ommatidia (unit eyes) are classified into two subtypes, known as ‘pale’ or ‘yellow’, depending on Rhodopsin expression in R7 and R8. Subtype specification is controlled by a stochastic decision in R7 and instructed to the underlying R8. We find that the Activin receptor Baboon is required in R8 to receive non-redundant signaling from the three Activin ligands, activating the transcription factor dSmad2. Concomitantly, two BMP ligands activate their receptor, Thickveins, and the transcriptional effector, Mad. The Amon TGFβ processing factor appears to regulate components of the TGFβ pathway specifically in pale R7. Mad and dSmad2 cooperate to modulate the Hippo pathway kinase Warts and the growth regulator Melted; two opposing factors of a bi-stable loop regulating R8 Rhodopsin expression. Therefore, TGFβ and growth pathways interact in postmitotic cells to precisely coordinate cell-specific output.

scholarly journals Regulation of the Hippo Pathway Transcription Factor TEAD

2017 ◽  
Vol 42 (11) ◽  
pp. 862-872 ◽  
Author(s):  
Kimberly C. Lin ◽  
Hyun Woo Park ◽  
Kun-Liang Guan
Keyword(s):  
Transcription Factor ◽  
Hippo Pathway ◽  
The Hippo Pathway

scholarly journals Amotl2a interacts with the Hippo effector Yap1 and the Wnt/β-catenin effector Lef1 to control tissue size in zebrafish

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Sobhika Agarwala ◽  
Sandra Duquesne ◽  
Kun Liu ◽  
Anton Boehm ◽  
Lin Grimm ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Cell Junction ◽  
Hippo Signaling ◽  
Sensory Organs ◽  
Hippo Signaling Pathway ◽  
Tissue Size ◽  
The Hippo Pathway ◽  
First Time

During development, proliferation must be tightly controlled for organs to reach their appropriate size. While the Hippo signaling pathway plays a major role in organ growth control, how it senses and responds to increased cell density is still unclear. In this study, we use the zebrafish lateral line primordium (LLP), a group of migrating epithelial cells that form sensory organs, to understand how tissue growth is controlled during organ formation. Loss of the cell junction-associated Motin protein Amotl2a leads to overproliferation and bigger LLP, affecting the final pattern of sensory organs. Amotl2a function in the LLP is mediated together by the Hippo pathway effector Yap1 and the Wnt/β-catenin effector Lef1. Our results implicate for the first time the Hippo pathway in size regulation in the LL system. We further provide evidence that the Hippo/Motin interaction is essential to limit tissue size during development.

scholarly journals The Ets Transcription Factor GABP Is a Component of the Hippo Pathway Essential for Growth and Antioxidant Defense

Cell Reports ◽  
2013 ◽  
Vol 3 (5) ◽  
pp. 1663-1677 ◽  
Author(s):  
Hongtan Wu ◽  
Yubo Xiao ◽  
Shihao Zhang ◽  
Suyuan Ji ◽  
Luyao Wei ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Antioxidant Defense ◽  
Hippo Pathway ◽  
Ets Transcription Factor ◽  
The Hippo Pathway

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.

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