The Tumor-Suppressor Gene fat Controls Tissue Growth Upstream of Expanded in the Hippo Signaling Pathway

Silva, Elizabeth; Tsatskis, Yonit; Gardano, Laura; Tapon, Nicolas; McNeill, Helen

doi:10.1016/j.cub.2006.09.004

Cited by 265 publications

(287 citation statements)

References 44 publications

(70 reference statements)

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“…In addition, Pez may activate the Hippo pathway by binding to Kibra (Poernbacher et al, 2012). The Fat protocadherin, a cell surface molecule, was also identified as an upstream regulator of the Hippo pathway (Bennett and Harvey, 2006;Cho et al, 2006;Silva et al, 2006;Willecke et al, 2006;Tyler and Baker, 2007). Removing one copy of yki dramatically suppressed the fat mutant overgrowth phenotype (Bennett and Harvey, 2006;Silva et al, 2006;Willecke et al, 2006), indicating that yki is an important mediator of fat function.…”

Section: The Drosophila Hippo Pathwaymentioning

confidence: 99%

“…The Fat protocadherin, a cell surface molecule, was also identified as an upstream regulator of the Hippo pathway (Bennett and Harvey, 2006;Cho et al, 2006;Silva et al, 2006;Willecke et al, 2006;Tyler and Baker, 2007). Removing one copy of yki dramatically suppressed the fat mutant overgrowth phenotype (Bennett and Harvey, 2006;Silva et al, 2006;Willecke et al, 2006), indicating that yki is an important mediator of fat function. Fat activity is regulated by binding to another protocadherin, Dachsous (Ds) (Matakatsu and Blair, 2006), and is modulated by several proteins such as the casein kinase Discs overgrown (Dco) (Feng and Irvine, 2009;Sopko et al, 2009), the Golgi-resident kinase Four-jointed (Fj) (Rogulja et al, 2008;Willecke et al, 2008;Simon et al, 2010), and the Fat/Ds-interacting protein Lowfat (Lft) (Mao et al, 2009).…”

Section: The Drosophila Hippo Pathwaymentioning

confidence: 99%

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The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

et al. 2012

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This pathway was first found to inhibit cell proliferation and promote apoptosis, therefore regulating cell number and organ size in both Drosophila and mammals. However, in several organs, disturbance of the pathway leads to specific expansion of the progenitor cell compartment and manipulation of the pathway in embryonic stem cells strongly affects their self-renewal and differentiation. In this review, we summarize current observations on roles of the Hippo pathway in different types of stem cells and discuss how these findings changed our view on the Hippo pathway in organ development and tumorigenesis.

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Section: The Drosophila Hippo Pathwaymentioning

confidence: 99%

Section: The Drosophila Hippo Pathwaymentioning

confidence: 99%

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

et al. 2012

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“…The NF2 tumor suppressor, also known as Merlin (Mer), and Expanded (Ex), two ezrin/radixin/moesin (ERM) family actin-binding proteins (McClatchey and Giovannini 2005;Okada et al 2007), have been shown to positively regulate the Hippo pathway in Drosophila . Interestingly, genetic data indicate that Fat, a protocadherin tumor suppressor, also functions upstream of Hpo (Bennett and Harvey 2006;Cho et al 2006;Hariharan 2006;Silva et al 2006;Willecke et al 2006;Tyler and Baker 2007;Yin and Pan 2007). The fact that Fat may interact with another protocadherin, Dachsous, at the cell surface (Matakatsu and Blair 2004;Halbleib and Nelson 2006) suggests an exciting possibility that the Hippo pathway may be involved in cell growth regulation in response to cell-cell contact.…”

mentioning

confidence: 99%

Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control

Zhao¹,

Wei²,

Li³

et al. 2007

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“…Upon binding to Ds and subsequent phosphorylation by the kinase Disc Overgrown (Dco), Ft is thought to antagonize Wts degradation via the myosin Dachs. 25,26 Finally, the actin cytoskeleton has been reported to promote Yki activity (or that of its mammalian counterpart YAP -Yes-activated protein), representing a possible mechanical input into Hippo signaling. [27][28][29][30] Although some key molecular mechanisms that regulate Hippo signaling have been identified, many aspects of how these are modulated under physiological or stress conditions remain poorly explored.…”

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confidence: 99%

The Hippo pathway promotes cell survival in response to chemical stress

Cara

Maile²,

Parsons

et al. 2015

Cell Death Differ

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Cellular stress defense mechanisms have evolved to maintain homeostasis in response to a broad variety of environmental challenges. Stress signaling pathways activate multiple cellular programs that range from the activation of survival pathways to the initiation of cell death when cells are damaged beyond repair. To identify novel players acting in stress response pathways, we conducted a cell culture RNA interference (RNAi) screen using caffeine as a xenobiotic stress-inducing agent, as this compound is a well-established inducer of detoxification response pathways. Specifically, we examined how caffeine affects cell survival when Drosophila kinases and phosphatases were depleted via RNAi. Using this approach, we identified and validated 10 kinases and 4 phosphatases that are essential for cell survival under caffeine-induced stress both in cell culture and living flies. Remarkably, our screen yielded an enrichment of Hippo pathway components, indicating that this pathway regulates cellular stress responses. Indeed, we show that the Hippo pathway acts as a potent repressor of stress-induced cell death. Further, we demonstrate that Hippo activation is necessary to inhibit a pro-apoptotic program triggered by the interaction of the transcriptional co-activator Yki with the transcription factor p53 in response to a range of stress stimuli. Our in vitro and in vivo loss-of-function data therefore implicate Hippo signaling in the transduction of cellular survival signals in response to chemical stress. Throughout their lives, organisms are exposed to a wide range of harmful substances. These compounds, often referred to as xenobiotics, may enter the body through direct contact, inhalation or ingestion, and can originate from many sources including pharmaceuticals, pesticides, plant toxins and pollutants. The ubiquitous and varied nature of xenobiotic pressure is reflected in the complexity of conserved cellular defense mechanisms that respond to these chemical compounds, and metazoans have thus developed a range of pathways that activate survival responses or trigger programmed cell death to eliminate damaged cells. 1 Xenobiotic pathways control the expression and activation of heat shock proteins, oxidative stress components, DNA repair enzymes, hypoxia response factors and several groups of xenobiotic-metabolizing enzymes. In eukaryotes, environmental challenges that activate stress response programs are relayed through a complex signaling cascade. Some stress pathways respond to very specific compounds, whereas others, such as those depending on Mitogen-activated protein kinases, propagate stress signals from a broad spectrum of stimuli. 1-3 Despite the importance that stress response pathways play in pharmacology and toxicology, we still have a relatively poor understanding of the complex networks that launch these cellular defense systems.We performed a quantitative cell-culture RNA interference (RNAi) assay of Drosophila kinases and phosphatases to identify key regulators of stress response pathways that reac...

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The Tumor-Suppressor Gene fat Controls Tissue Growth Upstream of Expanded in the Hippo Signaling Pathway

Abstract: Together, these data suggest that Fat functions as a cell-surface receptor for the Expanded branch of the conserved Hippo growth control pathway.

Cited by 265 publications

References 44 publications

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control

The Hippo pathway promotes cell survival in response to chemical stress

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