Regulation of the Hippo pathway by cell architecture and mechanical signals

Schroeder, Molly C.; Halder, Georg

doi:10.1016/j.semcdb.2012.06.001

Cited by 117 publications

(110 citation statements)

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“…For example, it was recently shown that YAP and TAZ are activated by cell shape, cytoskeletal, and mechanical cues independent of its upstream kinases Mst1/2 and LATS1/2 (11,28,29). Therefore, it has been suggested that YAP and TAZ are central players of the Hippo pathway and different stimuli may induce various biologic changes by regulating YAP/TAZ through multiple signaling pathways (30).…”

Section: Discussionmentioning

confidence: 99%

YAP-Induced Resistance of Cancer Cells to Antitubulin Drugs Is Modulated by a Hippo-Independent Pathway

et al. 2014

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Although antitubulin drugs are used widely to treat human cancer, many patients display intrinsic or acquired drug resistance that imposes major obstacles to successful therapy. Mounting evidence argues that cancer cell apoptosis triggered by antitubulin drugs relies upon activation of the cell-cycle kinase Cdk1; however, mechanistic connections of this event to apoptosis remain obscure. In this study, we identified the antiapoptotic protein YAP, a core component of the Hippo signaling pathway implicated in tumorigenesis, as a critical linker coupling Cdk1 activation to apoptosis in the antitubulin drug response. Antitubulin drugs activated Cdk1, which directly phosphorylated YAP on five sites independent of the Hippo pathway. Mutations in these phosphorylation sites on YAP relieved its ability to block antitubulin drug-induced apoptosis, further suggesting that YAP was inactivated by Cdk1 phosphorylation. Notably, we found that YAP was not phosphorylated and inactivated after antitubulin drug treatment in taxol-resistant cancer cells. Our findings suggest YAP and its phosphorylation status as candidate prognostic markers in predicting antitubulin drug response in patients. Cancer Res; 74(16); 4493-503. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

YAP-Induced Resistance of Cancer Cells to Antitubulin Drugs Is Modulated by a Hippo-Independent Pathway

et al. 2014

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“…Many types of polarity machineries, such as adherens junctions, tight junctions, the Mer/Ex/Kibra complex, Crumbs (Crb), the Par complex, and Fat/Dachsous, are involved in this action to maintain the differentiation and morphology of the epithelium in a partially redundant manner. This subject has been comprehensively reviewed elsewhere (Schroeder and Halder 2012;. Recent studies show that loss of Spectrin, a contractile protein at the cytoskeleton-membrane interface, also generates Hpo mutant-like tissue overgrowth phenotypes in Drosophila wings and eyes, which are likely due to dysregulated cytoskeleton tension Fletcher et al 2015;Wong et al 2015).…”

Section: Cell Polarity and Architecturementioning

confidence: 99%

Mechanisms of Hippo pathway regulation

2016

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The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell–cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

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“…There is little information about the molecular devices that can sense this physical property, but once the outer cells form an epithelium there are hints as to how this can be transmitted to the nucleus to mediate differential gene expression. The Hippo pathway, which is under the control of cell polarity cues and is able to sense cell density and associated physical parameters (Schroeder and Halder, 2012), is active in inner cells of the morula, where it inhibits Tead4 activity through cytoplasmic sequestration of its co-factor Yap (Yap1). In outside cells Hippo signalling is low, allowing Yap to translocate to the nucleus and, together with Tead4, to promote Cdx2 expression (Nishioka et al, 2009).…”

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confidence: 99%

A molecular basis for developmental plasticity in early mammalian embryos

2013

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SummaryEarly mammalian embryos exhibit remarkable plasticity, as highlighted by the ability of separated early blastomeres to produce a whole organism. Recent work in the mouse implicates a network of transcription factors in governing the establishment of the primary embryonic lineages. A combination of genetics and embryology has uncovered the organisation and function of the components of this network, revealing a gradual resolution from ubiquitous to lineage-specific expression through a combination of defined regulatory relationships, spatially organised signalling, and biases from mechanical inputs. Here, we summarise this information, link it to classical embryology and propose a molecular framework for the establishment and regulation of developmental plasticity. Key words: Chimaera, Developmental plasticity, Regulative development, Stochastic gene expression, Twin IntroductionOne of the most intriguing observations in developmental biology was reported by Hans Driesch in 1892 when testing the dogma of the time, which had been established by W. Roux (Roux, 1888; see Sander, 1991), that potencies, or 'prospective cell fates' (see Glossary, Box 1) as we call them today, are progressively and irreversibly restricted from the first cleavage of an embryo (Driesch, 1892). Driesch established a clean experimental protocol to split the early blastomeres of sea urchin embryos and analyse their fates during development. Not without surprise he observed that, upon separation, individual blastomeres from the 2-and 4-cell stages could give rise to a complete sea urchin larva (Fig. 1A). This indicated that the fates of the first blastomeres were not fixed, as had been suggested by Roux, but exhibited a large degree of plasticity (see Glossary, Box 1), i.e. the blastomeres were totipotent (Sander, 1991;Sander, 1992). As a result of these experiments he could experimentally induce twins and quadruplets. Similar results were obtained through related experiments in other embryos, including frogs (Morgan, 1895) -which had been the subject of Roux's work -revealing that the full developmental potential of the zygote (totipotency, see Glossary, Box 1) is maintained through at least the first divisions of the embryo.These experiments highlight a transient maintenance of developmental potential (see Glossary, Box 1), which is not restricted to the early stages of development, and indicate that, within an embryo, the potential of a cell or group of cells is greater than its actual fate (Fig. 1B) (Wolpert and Tickle, 2011). Furthermore, this potential can be captured and replicated, as in the Development 140, 3499-3510 (2013) HYPOTHESIS Box 1. GlossaryCell fate. The developmental destination of a cell if left undisturbed in its environment. It is revealed through lineagetracing experiments in which a cell is labelled and its progeny followed. The fate of a cell is more restricted than its potential. Cell state. A transient condition with a variable degree of stability; a stepping stone in the chain that configures a path to ...

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Regulation of the Hippo pathway by cell architecture and mechanical signals

Cited by 117 publications

References 111 publications

YAP-Induced Resistance of Cancer Cells to Antitubulin Drugs Is Modulated by a Hippo-Independent Pathway

YAP-Induced Resistance of Cancer Cells to Antitubulin Drugs Is Modulated by a Hippo-Independent Pathway

Mechanisms of Hippo pathway regulation

A molecular basis for developmental plasticity in early mammalian embryos

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