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The Hippo Kinase Pathway: a master regulator of proliferation, development and differentiation

The Hippo Kinase Pathway: a master regulator of proliferation, development and differentiation

 

Federica Lo Sardo1, Sabrina Strano2 and Giovanni Blandino1

1 Translational Oncogenomic Unit, Regina Elena Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy.
Electronic address: losardo@ifo.it ; blandino@ifo.it
2 Molecular Chemoprevention Unit, Italian National Cancer Institute "Regina Elena", 00144 Rome, Italy.
Electronic address: strano@ifo.it

 

May 2014

 

Abstract

Hippo signaling transduction pathway is widely conserved through evolution and controls cell growth, homeostasis, apoptosis, commitment, differentiation and senescence. It consists of a conserved kinase cascade whose final targets are the transcriptional coactivator Yorkie (Yki) in Drosophila and the homologues YAP and TAZ in mammals. These transcriptional coactivators are unable to bind DNA per se, and can regulate the activity of their target genes only in association with transcription factors. In Drosophila, Yki associates with the transcription factors Sd and Hth regulating pro-proliferative and anti-apoptotic genes. In mammals instead, YAP/TAZ can associate with several distinct transcription factors. This depends from the type of signals to which cells are subjected, the cell type and the developmental stage. The transcriptional outcome resulting from this association can be either pro-apoptotic or pro-proliferative. Hippo pathway dysregulation has been associated with several pathologic conditions (tissue overgrowth, developmental defects and cancer). In particular, solid tumors show an upregulation or hyperactivation of YAP/TAZ, while several hematologic tumors are associated with YAP downregulation. This might suggest that the Hippo pathway holds the potential to be an attractive target for novel therapeutic approaches for cancer.


Introduction

Hippo signal transduction pathway is an evolutionary conserved pathway, from flies to humans, that controls organ size, development, tissue regeneration-homeostasis and stem cell self-renewal through the regulation of cell proliferation, cell commitment and apoptosis. Components of the pathway include membrane associated proteins that sense cell polarity, cell density and mechanical cues, that in turn activate a cascade of kinases whose final target is the transcriptional coactivator Yorkie (Yki) in Drosophila, or its mammalian counterparts Yes Associated Protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ, also called WWTR1). These factors are unable to bind DNA per se, but can regulate transcription in association with other transcription factors.

Aberrant regulation of the Hippo pathway is associated with tissue overgrowth and various types of cancers in mammals (see below). Thus, a major comprehension of the mechanisms at the basis of YAP/TAZ upstream regulation and downstream transcriptional response could also be relevant for the characterization of prognostic factors in cancer and for the development of novel anti-cancer therapies.


Hippo pathway core components

The core components of the Hippo pathway were firstly discovered in Drosophila melanogaster by mosaic genetic screens which showed a strong overgrowth phenotype shared by loss-of-function mutants. Based on these findings, the Hippo pathway had been defined as an oncosuppressor pathway. In parallel, homologous components of the pathway were discovered in other organisms, including mammals (reviewed in Varelas and Wrana, 2012). Some of them are able to rescue mutant phenotypes in flies (Lai et al., 2005; Tao et al., 1999; Wu et al., 2003). The Hippo pathway core components are listed in table 1 and schematically represented in Figure 1.

Table 1: Hippo pathway core components


Figure 1. Schematic representation of Hippo pathway core components: their upstream regulators and transcriptional outcome in Drosophila (left) and mammals (right). In figure1, the Extracellular Matrix (ECM), the cytoplasm and the nucleus of cells are represented. Proteins are represented in various colours, with homologous components between Drosophila and mammals represented with the same colour. Black arrows indicate activation, while blunt lines indicate inhibition. Light blue arrows indicate phosphorylation of proteins by kinases. Orange balls indicate phosphorylation sites of target proteins. The Hippo pathway core kinase cassette is represented inside a black rectangle. For simplicity, junction proteins and polarity proteins are not represented by the specific Drosophila or mammalian subunits. In general, even if they are represented by different complexes in Drosophila or mammals, either homologous or not, they inhibit Yki and YAP/TAZ nuclear activity by sequestering them at the apical membrane or by interacting with and activating the Hippo pathway core kinases (represented in the black rectangle) that in turn inhibit Yki and YAP/TAZ nuclear activity. In mammals, GPCR signalling and mechanical stress coming from the ECM activate Rho GTPase that in turn stabilizes the actin cytoskeleton thus inhibiting Hippo pathway core kinases (and activating YAP/TAZ nuclear activity).In the nucleus, Drosophila Yki interacts with Sd or Hth transcription factors and activates pro-proliferative and anti-apoptotic genes. Mammalian YAP and TAZ instead interact with several different transcription factors (see also table 3) and the resulting transcriptional outcome may be either pro-proliferative or pro-apoptotic. This might depend from the incoming signals to which cells are exposed and from the specificity of the associated transcription factor.

They include two serine/threonine kinases associated with adaptor proteins: the first is the STE20 kinase Hippo (Hpo) with the adaptor protein Salvador (Sav) (MST1/2 and Sav1 in mammals) (Callus et al., 2006; Harvey et al., 2003; Jia et al., 2003; Kango-Singh et al., 2002; Pantalacci et al., 2003; Tapon et al., 2002; Udan et al., 2003; Wu et al., 2003), and the second is the NDR kinase Warts (Wts) associated with the scaffold protein Mats, (Lats1/2 associated with Mob1 in mammals) (Callus et al., 2006; Chan et al., 2005; Praskova et al., 2008; Wu et al., 2003). Drosophila Hpo and mammalian MST1/2 directly bind Sav protein and are able to phosphorylate and activate Sav itself and Mats (Sav1 and Mob1 mammalian counterparts).
Drosophila Mats and mammalian Mob1 interact with and phosphorylate Wts and Lats1/2, respectively. Wts-Mats and Lats1/2-Mob phosphorylate in turn specific residues of the transcriptional coactivator Yki and its mammalian counterparts YAP and TAZ. Yki and YAP/TAZ phosphorylation result in their cytoplasmic sequestration via 14-3-3 binding (Dong et al., 2007; Haoet al., 2008; Kanai et al., 2000; Lei et al., 2008; Vassilev et al., 2001; Zhao et al., 2007), which inhibits TAZ/YAP nuclear functions as transcriptional coactivators, while promoting their cytoplasmic role (Varelas et al., 2010) or their proteasomal degradation (Liu et al., 2010; Zhao et al., 2010).
It is becoming clear that not only Hippo pathway core kinases are able to regulate YAP and TAZ nuclear activity. For example, recently it has been shown that SIRT1 protein is able to activate YAP2 isoform by deacetylation in hepatocellular carcinoma cells (HCC) (Mao et al., 2014). Moreover, YAP and TAZ are at the crossroad between several other signalling pathways as Wnt, Tgfβ and Notch (reviewed in Barry and Camargo, 2013).
Conversely, Hippo pathway core components may be involved in cell cycle control independently of YAP/TAZ regulation. For example, Mst1 has been shown to promote apoptosis in injuried cardiomiocytes independently of YAP phosphorylation (Maejima et al., 2013). In this case, Mst1 has been shown to phosphorylate beclin1, a protein that alternatively binds Atg14L-Vps34 or Bcl-2 protein. In normal conditions, beclin1 complexes with Atg14L-Vps34 to promote autophagy, a process required for the recycling of macromolecular proteins and damaged organelles. Meanwhile, Bcl-2 sequesters Bax and inhibits apoptosis. Mst1 phosphorylates Beclin1 at Thr108 during cellular stress. This causes Beclin1 dissociation from Atg14L-Vps34 and its association with Bcl-2 that is no more able to sequester Bax. This in turn leads to apoptosis.


Upstream regulators of Hippo pathway core components

Proteins involved in cell junction, cell polarity and G-protein-coupled receptor (GPCR) signalling are upstream regulators of the core Hippo pathway. These proteins regulate YAP/TAZ nuclear activity in response to both mechanical and biochemical stimuli originated from the extracellular matrix (ECM).

Cell junction/cell polarity: in vivo, epithelial cells are in contact each another through specialized cellular junctions, forming sheets that line the surface of the animal body and internal cavities (for example digestive and circulatory cavities). These cells are oriented in the space with an apical-basal polarity: the apical membrane is oriented to the outside surface of the body, or the lumen of internal cavities, and the basolateral membrane is oriented away from the lumen. Polarity proteins associate with junction proteins in order to contribute to their proper localization and assembly and thereby to the functional organization of the tissues. The Kibra complex, conserved in Drosophila and in mammals, represents an example of apical proteins involved in Hippo pathway regulation. It recruits Hippo pathway core components like Hpo and Sav to the apical plasma membrane for activation, thus inhibiting YAP/TAZ nuclear activity and tissue growth (Genevet et al., 2010; Yu et al., 2010). Also the Crumbs polarity complex, the Scribble complex and Par3 polarity complex have been shown to be negative regulators of YAP and TAZ nuclear function (Chen et al., 2010; Gurvich et al., 2010; Ling et al., 2010; Robinson et al., 2010; Varelas et al., 2010). Other polarity proteins as Ajuba and LKB1 have been shown to negatively regulate YAP and TAZ nuclear function (Das Thakur et al., 2010; Nguyen et al., 2013). Moreover, many cell junction associated proteins, such as angiomotin (AMOT), MPDZ, PATJ, PALS1, LIN7C, PTPN14, ZO-1, a-β-catenin and E-cadherin have been identified as interacting partners or regulators of Hippo pathway core components (Kim et al., 2011; Liu et al., 2013b; Oka et al., 2010; Remue et al., 2010; Schlegelmilch et al., 2011; Zhao et al., 2011).

In general, these proteins negatively regulate YAP/TAZ nuclear function by sequestering YAP/TAZ to the apical plasma membrane, thus excluding them from the nucleus, and by interacting with and activating hippo pathway core kinases. This in turn inhibits YAP and TAZ nuclear function by phosphorylation (Genevet et al., 2010; Varelas et al., 2010; Yu et al., 2010; Zhao et al., 2011). Indeed, disruption of cellular junctions or downregulation of cell polarity/cell junction proteins leads to YAP/TAZ activation (Chen et al., 2010; Cordenonsi et al., 2011; Dupont et al., 2011; Varelas et al., 2010). Thus, YAP and TAZ nuclear function is inhibited by cell contact to finely tune the proliferation of cells within a tissue and an organ during physiological tissue-organ growth and regeneration. However, there are few exception to this rule: NPHP4 (nephronophthisis 4) can interact with and inhibit Lats1 (Habbig et al., 2011) and ZO-2 (zona occludens-2) can induce YAP nuclear localization (Oka et al., 2010). The regulation of Hippo pathway by apical-basal polarity and cell junction is largely conserved in Drosophila and mammals, even if not all the proteins are conserved between flies and vertebrates (Bossuyt et al., 2014).

Biochemical signals: very recently, several groups have shown that diffusible signals and metabolites like LPA, S1P, thrombin and statins regulate YAP/TAZ function (Miller et al., 2012; Mo et al., 2012; Sorrentino et al., 2014; Yu et al., 2012). LPA, S1P and thrombin activate G-protein coupled receptor (GPCR) which usually activate downstream signalling through heterotrimeric G proteins that in turn activate the mediator Rho GTPase. Depending on which Gα protein is activated, YAP and TAZ may be either activated or repressed. In fact, Gα12/13-, Gαq/11-, or Gαi/o-coupled signals induce YAP/TAZ activity, whereas Gαs-coupled signals repress YAP/TAZ activity (Mo et al., 2012; Yu et al., 2012). Rho GTPase are also regulated by mevalonate pathway. Recently in Sorrentino lab it has been shown that statins, by inhibiting the mevalonate biosynthesis, prevent Rho GTPase activation and thus Yki and YAP/TAZ nuclear function (Sorrentino et al., 2014).

Mechanical cues: in vivo, cells are subjected to mechanical stimulation coming from neighbouring cells, the ECM and surrounding biological fluids. These signals influence cell proliferation and migration, and cytoskeletal changes are at the basis of cellular responses to these mechanical stimuli. It has been recently shown that YAP and TAZ are regulated by changes in the actin cytoskeleton in response to mechanical cues experienced by the cell. In particular, cell adhesion, cell geometry, cell shape, cell suspension and extracellular matrix stiffness have been shown to regulate YAP/TAZ nuclear activity in different experimental reports. When cells are grown at low cell density, or on a stiff extracellular substrate, or also on a large adhesive island, conditions where the cell-ECM contact area is broad and the cytoskeleton is subjected to a stronger mechanical stimulation YAP and TAZ are predominantly localized in the nucleus. Conversely, YAP/TAZ effectors translocate to the cytplasm in response to high cellular density/cell contact, on a soft extracellular substrate or on micropatterned small islands, conditions in which the cell experience a small cell-ECM contact area and a low mechanical stress. (Dupont et al., 2011; Wada et al., 2011; Zhao et al., 2012; Zhao et al., 2007) . YAP and TAZ are not only mechanosensors, but also mechanoeffectors because, once activated, they are able to regulate in turn genes involved in extracellular matrix remodelling (Calvo et al., 2013).

It is still not completely clear how mechanical and biochemical cues experienced by the cell are linked with YAP and TAZ activity. It has been shown that both RHO GTPases and the actin cytoskeleton are able to transduce these upstream signals to YAP and TAZ. In particular, F-actin stabilization and RHO-GTPase activation (depending on the activated Gα protein) are able to activate YAP/TAZ, while F-actin destabilization determines YAP/TAZ inhibition. However, the gap between YAP and TAZ and these upstream transducers remains to be fulfilled.


YAP-TAZ effectors and their transcriptional targets

YAP mRNA is ubiquitously expressed in a wide range of mammalian tissues, with the exception of peripheral blood leukocytes (Komuro et al., 2003), it is expressed in all developmental stages from blastocyst to perinatal and it is necessary for a correct and vital embryonic development. TAZ instead shows a later onset, it is present in all the embryonic stages with the exception of blastocyst stage (Morin-Kensicki et al., 2006). YAP and TAZ per se are not able to bind DNA, but they regulate gene targets expression (either by activation or repression) through interaction with transcription factors in a tissue and development specific manner. By now, several YAP and TAZ interacting proteins have been characterized among which some are able to sequester or post-transcritpionally modify YAP and TAZ (table2) (Chan et al., 2011; Chen and Sudol, 1995; Espanel and Sudol, 2001; Howell et al., 2004; Hsu and Lawlor, 2011; Koontz et al., 2013; Mohler et al., 1999; Rosenbluh et al., 2012; Sudol, 1994; Tsutsumi et al., 2013), others are transcriptional regulators (table3) (Cui et al., 2003; Di Palma et al., 2009; Ferrigno et al., 2002; Hong et al., 2005; Hsu and Lawlor, 2011; Jeong et al., 2010; Kang et al., 2009; Murakami et al., 2005; Wang et al., 2013a; Xiao et al., 2013; Yagi et al., 1999). All the components of the Hippo pathway, from the membrane associated proteins to the cytoplasmic kinase cascade to the final effectors YAP and TAZ, are characterized by specific protein-protein interaction domains, among which the most common are WW domain and the similar SH3 domain, able to bind short peptides that are prolin-rich and often terminate with Tyrosine (Y), named PpxY motifs (Sudol and Hunter, 2000).

Table 2: YAP/TAZ interactors in mammals (regulative proteins)

Table 3: YAP/TAZ interactors in mammals (transcription factors).

There are two major YAP splicing variants with one (YAP1) or two (YAP2) WW domains, but recently, eight different spliced mRNA isoforms of YAP1 gene have been characterized and identified in a panel of human tissues (Gaffney et al., 2012). The different splicing variants of YAP, the different post-transcriptional modifications of YAP and TAZ, and the different chromatin state of target genes may select different repertoires of proteins in transcriptional complexes and affect the gene expression program in a developmental and tissue-specific manner (Beyer et al., 2013; Reginensi et al., 2013; Slattery et al., 2013).
The transcription factors with which YAP and TAZ cooperate are directly involved in control of cell proliferation/survival or apoptosis, like TEAD (Chan et al., 2009; Mahoney et al., 2005; Ota and Sasaki, 2008; Vassilev et al., 2001; Zhang et al., 2009; Zhao et al., 2008) and p73 transcription factors, (Strano et al., 2001) or are components of other signalling pathways as Wnt, EGFR, JAK/Stat, BMP-TGFbeta involved in embryonic development and adult tissue homeostasis. For example, it has been shown that YAP/TAZ interact with Smad proteins (Smad1, Smad2, Smad3) to enhance the transcription of genes responsive to BMP-TGFbeta signalling (Alarcon et al., 2009; Schlegelmilch et al., 2011; Varelas et al., 2010). Other transcriptional targets are represented by components of the Hippo pathway.


The dual role of YAP as an oncoprotein or an oncosuppressor

A lot of studies supported the functional conservation of the core Hippo pathway components between Drosophila and mammals in the control of cell proliferation.
When Hippo kinase pathway is inactive, YAP and TAZ enter the nucleus and affect transcription of different sets of target genes in a tissue and developmental specific manner (Beyer et al., 2013; Slattery et al., 2013). Increasing evidences showed that the transcriptional outcome in response to YAP/TAZ activation can be opposite. In mammals, it has been shown that YAP transcriptional coactivator can function either as an oncogene, or as a tumor suppressor, depending on the signals to which cells are subjected and on the transcription factors with which YAP is associated. The emerging and intriguing dual role of YAP and the mechanisms determining the two exclusive cellular responses (pro-proliferative or pro-apoptotic) are still not entirely understood as they were built on classic studies performed in different cell types and tissues. Here, we will discuss experimental evidences showing YAP as an oncogene or as an oncosuppressor.


YAP as an oncogene

There are several evidences supporting a pro-proliferative and pro-oncogenic role of YAP (and TAZ) in mammalian systems. In humans, YAP is present in the 11q22 amplicon that is amplified in a lot of solid tumors (Baldwin et al., 2005; Bashyam et al., 2005; Dai et al., 2003; Hermsen et al., 2005; Imoto et al., 2002; Imoto et al., 2001; Lambros et al., 2005; Overholtzer et al., 2006; Snijders et al., 2005; Weber et al., 1996) (Table 4). The syntenic chromosomal region in mouse contains YAP gene that is amplified in mammary and liver tumors (Overholtzer et al., 2006; Zender et al., 2006). Ectopic expression or hyperactivation of YAP promotes cell growth and induces oncogenic transformation and epithelial-mesenchimal transition (EMT) that is often associated with metastasis (Lamar et al., 2012; Lau et al., 2014; Nallet-Staub et al., 2013; Overholtzer et al., 2006; Zhao et al., 2009; Zhao et al., 2008).
In mouse, transgenic YAP overexpression or liver-specific knockout of Mst1/2 and Sav1 increases the number of stem/progenitor cells and determines liver overgrowth in a reversible manner, ultimately leading to hepatocellular carcinoma (HCC) (Camargo et al., 2007; Dong et al., 2007; Lee et al., 2010; Lu et al., 2010; Song et al., 2010; Zhou et al., 2009). Consistently, a lot of human cancers show overexpression or hyperactivation of nuclear YAP or TAZ or downregulation of Lasts1/2, Mst1/2 or Sav1 function (Dong et al., 2007; Hall et al., 2010; Jiang et al., 2006; Matsuura et al., 2011; Muramatsu et al., 2011; Nallet-Staub et al., 2013; Quan et al., 2014; Seidel et al., 2007; Steinhardt et al., 2008; Su et al., 2012; Takahashi et al., 2005; Wang et al., 2013b; Wang et al., 2012; Wang et al., 2010; Wierzbicki et al., 2013; Xu et al., 2011; Xu et al., 2009; Yuen et al., 2013; Zender et al., 2006; Zhao et al., 2007; Zhou et al., 2011b) see also table 4. Moreover, overexpression or hyperactivation of YAP and TAZ have been associated with poor prognosis and shorter survival times for patients in several human cancers (Hall et al., 2010; Liu et al., 2013a; Muramatsu et al., 2011; Wang et al., 2010; Xu et al., 2009; Zhang et al., 2011). It has been also shown that Mst1/2 and Sav1 knockout, or YAP activation expanded the stem and the progenitor cell population in the intestine and in the skin in mouse (Lee et al., 2008; Schlegelmilch et al., 2011; Zhou et al., 2011a). YAP has been shown to contribute also to the expansion of neuroprogenitor cells (Cao et al., 2008). In addition, YAP has been found to be upregulated in mouse Embryonic Stem cells (mES) and in induced pluripotent stem cells (iPS) and to contribute to their stemness by binding and activating a large number of genes known to be important for stem cell maintenance (Lian et al., 2010).

Table 4: Tumor tissues or tumor cell lines where.

TAZ is overexpressed in breast cancer stem cells and is required to maintain their self-renewal capacity, tumorigenicity and ability to promote the formation of metastasis (Bartucci et al., 2014; Chan et al., 2008; Cordenonsi et al., 2011). Moreover, YAP and TAZ have been recently found to be upregulated in mouse wounds and to be required for wound closure (Lee et al., 2014). Based on these results, YAP and TAZ are defined as oncogenes and as "stemness genes" (Ramalho-Santos et al., 2002).
TEAD transcription factors guides YAP and TAZ onto pro-proliferative genes (Chan et al., 2009; Lamar et al., 2012; Mahoney et al., 2005; Zhang et al., 2009; Zhao et al., 2008).


YAP as a tumor suppressor

We originally showed that the tumor suppressor p73 protein, which belongs to the p53 family, has been shown to guide YAP onto pro-apoptotic targets. These findings together with other evidences from diverse labs indicated that YAP might behave as a tumor suppressor, in particular upon DNA damage signalling and serum deprivation (Lapi et al., 2008; Oka et al., 2008; Strano et al., 2005; Strano et al., 2001; Yuan et al., 2008). p73-YAP interaction is increased upon DNA damage (Strano et al., 2005), where it has been shown to be phosphorylated by c-Abl that stabilizes both YAP and p73 and increases YAP/p73 interaction (Levy et al., 2008). On the other hand, p73-YAP interaction is inhibited upon Akt-mediated YAP phosphorylation (Basu et al., 2003). p73 is post-transcriptionally stabilized by YAP binding that competes with the E3 ubiquitin ligase ITCH, thereby preventing proteasomal degradation of p73 (Levy et al., 2007). YAP binding also induces p73 acetylation and transcriptional activity by recuiting the p300 acetyltranferase to target genes (Strano et al., 2005). Another oncosuppressor, PML (Promyelocytic leukemia protein) has been shown to act together with YAP and p73 as a mediator onto several proapoptotic target genes following DNA damage by physically interacting with both p73 and YAP (Bernassola et al., 2004; Lapi et al., 2008). PML is a key component and organizer of nuclear compartments termed nuclear bodies (NBs) implicated in processes such as transcriptional regulation, genome stability, response to viral infection, metabolism, apoptosis, and cell cycle control (reviewed in Gamell et al., 2014). It has also been proposed that PML partially collaborates with YAP and p73 in the proapoptotic response induced by DNA damage by several self-reinforcing mechanisms. First, YAP requires PML and NBs localization to coactivate p73 and, conversely, YAP and p73 are required for PML accumulation and PML-NB formation in response to DNA damage. Second, PML stabilizes YAP from proteasomal degradation by inducing its sumoylation and its recruitment into PML-nuclear bodies, where it collaborates with YAP and p73 onto target genes. Third, PML itself is a transcriptional target of YAP-p73-PML complex (Lapi et al., 2008; Strano et al., 2005).

Interestingly, it has been shown an important role for YAP in the regulation of cellular senescence in a functional cooperation with PML and p53 (Fausti et al., 2013; Xie et al., 2013).

Finally, while in many solid cancers YAP behaves as an oncogene and is upregulated or hyperactivated (see above), in hematologic malignancies, including lymphomas, leukemias and multiple myelomas YAP is deleted or downregulated. Lower YAP expression level correlates with poorer prognosis and shorter survival of patients (Cottini et al., 2014). In the context of hematologic malignancies, YAP downregulation is a mechanism by which cells escape apoptosis in the presence of DNA damage. In fact, in normal hematologic cells YAP is phosphorylated by c-abl that stabilizes YAP/p73 interaction and increases their transcriptional activity onto pro-apoptotic genes in the presence of DNA damage (Levy et al., 2007; Levy et al., 2008), while in malignant cells, where YAP is downregulated or absent, the c-Abl/p73/YAP axis is disrupted (Cottini et al., 2014). Collectively, these observations do not classify YAP as a real tumor suppressor, but as a transcriptional co-activator that can directly or indirectly regulate different tumor suppressor pathways (as p53 family or PML).

A better understanding of role the Hippo pathway in tumorigenesis assessed in different experimental and physiological/pathological conditions would be important for a more specific characterization of prognostic factors in cancer and for the development of anti-cancer therapies that often need to be adapted to the type of disease and to the individual patient.

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Nat Cell Biol. 2003 Oct;5(10):921-7. Epub 2003 Sep 21.
PMID 14502295
 
Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway.
Udan RS, Kango-Singh M, Nolo R, Tao C, Halder G.
Nat Cell Biol. 2003 Oct;5(10):914-20. Epub 2003 Sep 21.
PMID 14502294
 
hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts.
Wu S, Huang J, Dong J, Pan D.
Cell. 2003 Aug 22;114(4):445-56.
PMID 12941273
 
Ubiquitin-dependent degradation of p73 is inhibited by PML.
Bernassola F, Salomoni P, Oberst A, Di Como CJ, Pagano M, Melino G, Pandolfi PP.
J Exp Med. 2004 Jun 7;199(11):1545-57.
PMID 15184504
 
Heterogeneous nuclear ribonuclear protein U associates with YAP and regulates its co-activation of Bax transcription.
Howell M, Borchers C, Milgram SL.
J Biol Chem. 2004 Jun 18;279(25):26300-6. Epub 2004 Apr 19.
PMID 15096513
 
Multiple microalterations detected at high frequency in oral cancer.
Baldwin C, Garnis C, Zhang L, Rosin MP, Lam WL.
Cancer Res. 2005 Sep 1;65(17):7561-7.
PMID 16140918
 
Array-based comparative genomic hybridization identifies localized DNA amplifications and homozygous deletions in pancreatic cancer.
Bashyam MD, Bair R, Kim YH, Wang P, Hernandez-Boussard T, Karikari CA, Tibshirani R, Maitra A, Pollack JR.
Neoplasia. 2005 Jun;7(6):556-62.
PMID 16036106
 
The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1.
Chan EH, Nousiainen M, Chalamalasetty RB, Schafer A, Nigg EA, Sillje HH.
Oncogene. 2005 Mar 17;24(12):2076-86.
PMID 15688006
 
Chromosomal changes in relation to clinical outcome in larynx and pharynx squamous cell carcinoma.
Hermsen M, Alonso Guervos M, Meijer G, van Diest P, Suarez Nieto C, Marcos CA, Sampedro A.
Cell Oncol. 2005;27(3):191-8.
PMID 16037640
 
TAZ, a transcriptional modulator of mesenchymal stem cell differentiation.
Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, Mueller E, Benjamin T, Spiegelman BM, Sharp PA, Hopkins N, Yaffe MB.
Science. 2005 Aug 12;309(5737):1074-8.
PMID 16099986
 
Control of cell proliferation and apoptosis by mob as tumor suppressor, mats.
Lai ZC, Wei X, Shimizu T, Ramos E, Rohrbaugh M, Nikolaidis N, Ho LL, Li Y.
Cell. 2005 Mar 11;120(5):675-85.
PMID 15766530
 
Analysis of ovarian cancer cell lines using array-based comparative genomic hybridization.
Lambros MB, Fiegler H, Jones A, Gorman P, Roylance RR, Carter NP, Tomlinson IP.
J Pathol. 2005 Jan;205(1):29-40.
PMID 15586366
 
The transcriptional co-activator TAZ interacts differentially with transcriptional enhancer factor-1 (TEF-1) family members.
Mahoney WM Jr, Hong JH, Yaffe MB, Farrance IK.
Biochem J. 2005 May 15;388(Pt 1):217-25.
PMID 15628970
 
A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome.
Murakami M, Nakagawa M, Olson EN, Nakagawa O.
Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18034-9. Epub 2005 Dec 6.
PMID 16332960
 
Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma.
Snijders AM, Schmidt BL, Fridlyand J, Dekker N, Pinkel D, Jordan RC, Albertson DG.
Oncogene. 2005 Jun 16;24(26):4232-42.
PMID 15824737
 
The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage.
Strano S, Monti O, Pediconi N, Baccarini A, Fontemaggi G, Lapi E, Mantovani F, Damalas A, Citro G, Sacchi A, Del Sal G, Levrero M, Blandino G.
Mol Cell. 2005 May 13;18(4):447-59.
PMID 15893728
 
Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers.
Takahashi Y, Miyoshi Y, Takahata C, Irahara N, Taguchi T, Tamaki Y, Noguchi S.
Clin Cancer Res. 2005 Feb 15;11(4):1380-5.
PMID 15746036
 
Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation.
Callus BA, Verhagen AM, Vaux DL.
FEBS J. 2006 Sep;273(18):4264-76. Epub 2006 Aug 23.
PMID 16930133
 
Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma.
Jiang Z, Li X, Hu J, Zhou W, Jiang Y, Li G, Lu D.
Neurosci Res. 2006 Dec;56(4):450-8. Epub 2006 Oct 17.
PMID 17049657
 
Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65.
Morin-Kensicki EM, Boone BN, Howell M, Stonebraker JR, Teed J, Alb JG, Magnuson TR, O'Neal W, Milgram SL.
Mol Cell Biol. 2006 Jan;26(1):77-87.
PMID 16354681
 
Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon.
Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA.
Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12405-10. Epub 2006 Aug 7.
PMID 16894141
 
Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach.
Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, Fan ST, Luk JM, Wigler M, Hannon GJ, Mu D, Lucito R, Powers S, Lowe SW.
Cell. 2006 Jun 30;125(7):1253-67.
PMID 16814713
 
YAP1 increases organ size and expands undifferentiated progenitor cells.
Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, Brummelkamp TR.
Curr Biol. 2007 Dec 4;17(23):2054-60. Epub 2007 Nov 1.
PMID 17980593
 
Elucidation of a universal size-control mechanism in Drosophila and mammals.
Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, Gayyed MF, Anders RA, Maitra A, Pan D.
Cell. 2007 Sep 21;130(6):1120-33.
PMID 17889654
 
The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73.
Levy D, Adamovich Y, Reuven N, Shaul Y.
Cell Death Differ. 2007 Apr;14(4):743-51. Epub 2006 Nov 17.
PMID 17110958
 
Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma.
Seidel C, Schagdarsurengin U, Blumke K, Wurl P, Pfeifer GP, Hauptmann S, Taubert H, Dammann R.
Mol Carcinog. 2007 Oct;46(10):865-71.
PMID 17538946
 
Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.
Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, Zheng P, Ye K, Chinnaiyan A, Halder G, Lai ZC, Guan KL.
Genes Dev. 2007 Nov 1;21(21):2747-61.
PMID 17974916
 
YAP regulates neural progenitor cell number via the TEA domain transcription factor.
Cao X, Pfaff SL, Gage FH.
Genes Dev. 2008 Dec 1;22(23):3320-34. doi: 10.1101/gad.1726608. Epub 2008 Nov 17.
PMID 19015275
 
A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells.
Chan SW, Lim CJ, Guo K, Ng CP, Lee I, Hunziker W, Zeng Q, Hong W.
Cancer Res. 2008 Apr 15;68(8):2592-8. doi: 10.1158/0008-5472.CAN-07-2696.
PMID 18413727
 
Tumor suppressor LATS1 is a negative regulator of oncogene YAP.
Hao Y, Chun A, Cheung K, Rashidi B, Yang X.
J Biol Chem. 2008 Feb 29;283(9):5496-509. Epub 2007 Dec 24.
PMID 18158288
 
PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop.
Lapi E, Di Agostino S, Donzelli S, Gal H, Domany E, Rechavi G, Pandolfi PP, Givol D, Strano S, Lu X, Blandino G.
Mol Cell. 2008 Dec 26;32(6):803-14. doi: 10.1016/j.molcel.2008.11.019.
PMID 19111660
 
A crucial role of WW45 in developing epithelial tissues in the mouse.
Lee JH, Kim TS, Yang TH, Koo BK, Oh SP, Lee KP, Oh HJ, Lee SH, Kong YY, Kim JM, Lim DS.
EMBO J. 2008 Apr 23;27(8):1231-42. doi: 10.1038/emboj.2008.63. Epub 2008 Mar 27.
PMID 18369314
 
TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway.
Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y, Guan KL.
Mol Cell Biol. 2008 Apr;28(7):2426-36. doi: 10.1128/MCB.01874-07. Epub 2008 Jan 28.
PMID 18227151
 
Yap1 phosphorylation by c-Abl is a critical step in selective activation of proapoptotic genes in response to DNA damage.
Levy D, Adamovich Y, Reuven N, Shaul Y.
Mol Cell. 2008 Feb 15;29(3):350-61. doi: 10.1016/j.molcel.2007.12.022.
PMID 18280240
 
Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP).
Oka T, Mazack V, Sudol M.
J Biol Chem. 2008 Oct 10;283(41):27534-46. doi: 10.1074/jbc.M804380200. Epub 2008 Jul 17.
PMID 18640976
 
Mammalian Tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of Hippo signaling.
Ota M, Sasaki H.
Development. 2008 Dec;135(24):4059-69. doi: 10.1242/dev.027151. Epub 2008 Nov 12.
PMID 19004856
 
MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation.
Praskova M, Xia F, Avruch J.
Curr Biol. 2008 Mar 11;18(5):311-21. doi: 10.1016/j.cub.2008.02.006.
PMID 18328708
 
Expression of Yes-associated protein in common solid tumors.
Steinhardt AA, Gayyed MF, Klein AP, Dong J, Maitra A, Pan D, Montgomery EA, Anders RA.
Hum Pathol. 2008 Nov;39(11):1582-9. doi: 10.1016/j.humpath.2008.04.012. Epub 2008 Aug 13.
PMID 18703216
 
Yes-associated protein (YAP) functions as a tumor suppressor in breast.
Yuan M, Tomlinson V, Lara R, Holliday D, Chelala C, Harada T, Gangeswaran R, Manson-Bishop C, Smith P, Danovi SA, Pardo O, Crook T, Mein CA, Lemoine NR, Jones LJ, Basu S.
Cell Death Differ. 2008 Nov;15(11):1752-9. doi: 10.1038/cdd.2008.108. Epub 2008 Jul 11.
PMID 18617895
 
TEAD mediates YAP-dependent gene induction and growth control.
Zhao B, Ye X, Yu J, Li L, Li W, Li S, Yu J, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC, Guan KL.
Genes Dev. 2008 Jul 15;22(14):1962-71. doi: 10.1101/gad.1664408. Epub 2008 Jun 25.
PMID 18579750
 
Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways.
Alarcon C, Zaromytidou AI, Xi Q, Gao S, Yu J, Fujisawa S, Barlas A, Miller AN, Manova-Todorova K, Macias MJ, Sapkota G, Pan D, Massague J.
Cell. 2009 Nov 13;139(4):757-69. doi: 10.1016/j.cell.2009.09.035.
PMID 19914168
 
TEADs mediate nuclear retention of TAZ to promote oncogenic transformation.
Chan SW, Lim CJ, Loo LS, Chong YF, Huang C, Hong W.
J Biol Chem. 2009 May 22;284(21):14347-58. doi: 10.1074/jbc.M901568200. Epub 2009 Mar 26.
PMID 19324876
 
TAZ is a coactivator for Pax8 and TTF-1, two transcription factors involved in thyroid differentiation.
Di Palma T, D'Andrea B, Liguori GL, Liguoro A, de Cristofaro T, Del Prete D, Pappalardo A, Mascia A, Zannini M.
Exp Cell Res. 2009 Jan 15;315(2):162-75. doi: 10.1016/j.yexcr.2008.10.016. Epub 2008 Oct 28.
PMID 19010321
 
Glis3 is associated with primary cilia and Wwtr1/TAZ and implicated in polycystic kidney disease.
Kang HS, Beak JY, Kim YS, Herbert R, Jetten AM.
Mol Cell Biol. 2009 May;29(10):2556-69. doi: 10.1128/MCB.01620-08. Epub 2009 Mar 9.
PMID 19273592
 
Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma.
Xu MZ, Yao TJ, Lee NP, Ng IO, Chan YT, Zender L, Lowe SW, Poon RT, Luk JM.
Cancer. 2009 Oct 1;115(19):4576-85. doi: 10.1002/cncr.24495.
PMID 19551889
 
TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition.
Zhang H, Liu CY, Zha ZY, Zhao B, Yao J, Zhao S, Xiong Y, Lei QY, Guan KL.
J Biol Chem. 2009 May 15;284(20):13355-62. doi: 10.1074/jbc.M900843200. Epub 2009 Mar 26.
PMID 19324877
 
Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein.
Zhao B, Kim J, Ye X, Lai ZC, Guan KL.
Cancer Res. 2009 Feb 1;69(3):1089-98. doi: 10.1158/0008-5472.CAN-08-2997. Epub 2009 Jan 13.
PMID 19141641
 
Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene.
Zhou D, Conrad C, Xia F, Park JS, Payer B, Yin Y, Lauwers GY, Thasler W, Lee JT, Avruch J, Bardeesy N.
Cancer Cell. 2009 Nov 6;16(5):425-38. doi: 10.1016/j.ccr.2009.09.026.
PMID 19878874
 
The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila.
Chen CL, Gajewski KM, Hamaratoglu F, Bossuyt W, Sansores-Garcia L, Tao C, Halder G.
Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15810-5. doi: 10.1073/pnas.1004060107. Epub 2010 Aug 23.
PMID 20798049
 
Ajuba LIM proteins are negative regulators of the Hippo signaling pathway.
Das Thakur M, Feng Y, Jagannathan R, Seppa MJ, Skeath JB, Longmore GD.
Curr Biol. 2010 Apr 13;20(7):657-62. doi: 10.1016/j.cub.2010.02.035. Epub 2010 Mar 18.
PMID 20303269
 
Kibra is a regulator of the Salvador/Warts/Hippo signaling network.
Genevet A, Wehr MC, Brain R, Thompson BJ, Tapon N.
Dev Cell. 2010 Feb 16;18(2):300-8. doi: 10.1016/j.devcel.2009.12.011.
PMID 20159599
 
L3MBTL1 polycomb protein, a candidate tumor suppressor in del(20q12) myeloid disorders, is essential for genome stability.
Gurvich N, Perna F, Farina A, Voza F, Menendez S, Hurwitz J, Nimer SD.
Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22552-7. doi: 10.1073/pnas.1017092108. Epub 2010 Dec 13.
PMID 21149733
 
Hippo pathway effector Yap is an ovarian cancer oncogene.
Hall CA, Wang R, Miao J, Oliva E, Shen X, Wheeler T, Hilsenbeck SG, Orsulic S, Goode S.
Cancer Res. 2010 Nov 1;70(21):8517-25. doi: 10.1158/0008-5472.CAN-10-1242. Epub 2010 Oct 14.
PMID 20947521
 
TAZ as a novel enhancer of MyoD-mediated myogenic differentiation.
Jeong H, Bae S, An SY, Byun MR, Hwang JH, Yaffe MB, Hong JH, Hwang ES.
FASEB J. 2010 Sep;24(9):3310-20. doi: 10.1096/fj.09-151324. Epub 2010 May 13.
PMID 20466877
 
The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation.
Lian I, Kim J, Okazawa H, Zhao J, Zhao B, Yu J, Chinnaiyan A, Israel MA, Goldstein LS, Abujarour R, Ding S, Guan KL.
Genes Dev. 2010 Jun 1;24(11):1106-18. doi: 10.1101/gad.1903310.
PMID 20516196
 
The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis.
Lee KP, Lee JH, Kim TS, Kim TH, Park HD, Byun JS, Kim MC, Jeong WI, Calvisi DF, Kim JM, Lim DS.
Proc Natl Acad Sci U S A. 2010 May 4;107(18):8248-53. doi: 10.1073/pnas.0912203107. Epub 2010 Apr 19.
PMID 20404163
 
The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded.
Ling C, Zheng Y, Yin F, Yu J, Huang J, Hong Y, Wu S, Pan D.
Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10532-7. doi: 10.1073/pnas.1004279107. Epub 2010 May 24.
PMID 20498073
 
The hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCF{beta}-TrCP E3 ligase.
Liu CY, Zha ZY, Zhou X, Zhang H, Huang W, Zhao D, Li T, Chan SW, Lim CJ, Hong W, Zhao S, Xiong Y, Lei QY, Guan KL.
J Biol Chem. 2010 Nov 26;285(48):37159-69. doi: 10.1074/jbc.M110.152942. Epub 2010 Sep 21.
PMID 20858893
 
Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver.
Lu L, Li Y, Kim SM, Bossuyt W, Liu P, Qiu Q, Wang Y, Halder G, Finegold MJ, Lee JS, Johnson RL.
Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1437-42. doi: 10.1073/pnas.0911427107. Epub 2010 Jan 4.
PMID 20080689
 
Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling.
Oka T, Remue E, Meerschaert K, Vanloo B, Boucherie C, Gfeller D, Bader GD, Sidhu SS, Vandekerckhove J, Gettemans J, Sudol M.
Biochem J. 2010 Dec 15;432(3):461-72. doi: 10.1042/BJ20100870.
PMID 20868367
 
TAZ interacts with zonula occludens-1 and -2 proteins in a PDZ-1 dependent manner.
Remue E, Meerschaert K, Oka T, Boucherie C, Vandekerckhove J, Sudol M, Gettemans J.
FEBS Lett. 2010 Oct 8;584(19):4175-80. doi: 10.1016/j.febslet.2010.09.020. Epub 2010 Sep 18.
PMID 20850437
 
Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded.
Robinson BS, Huang J, Hong Y, Moberg KH.
Curr Biol. 2010 Apr 13;20(7):582-90. doi: 10.1016/j.cub.2010.03.019. Epub 2010 Apr 1.
PMID 20362445
 
Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression.
Song H, Mak KK, Topol L, Yun K, Hu J, Garrett L, Chen Y, Park O, Chang J, Simpson RM, Wang CY, Gao B, Jiang J, Yang Y.
Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1431-6. doi: 10.1073/pnas.0911409107. Epub 2010 Jan 8.
PMID 20080598
 
The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway.
Varelas X, Samavarchi-Tehrani P, Narimatsu M, Weiss A, Cockburn K, Larsen BG, Rossant J, Wrana JL.
Dev Cell. 2010 Dec 14;19(6):831-44. doi: 10.1016/j.devcel.2010.11.012.
PMID 21145499
 
Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer.
Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X.
Cancer Sci. 2010 May;101(5):1279-85. doi: 10.1111/j.1349-7006.2010.01511.x. Epub 2010 Jan 23.
PMID 20219076
 
Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded.
Yu J, Zheng Y, Dong J, Klusza S, Deng WM, Pan D.
Dev Cell. 2010 Feb 16;18(2):288-99. doi: 10.1016/j.devcel.2009.12.012.
PMID 20159598
 
A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP).
Zhao B, Li L, Tumaneng K, Wang CY, Guan KL.
Genes Dev. 2010 Jan 1;24(1):72-85. doi: 10.1101/gad.1843810.
PMID 20048001
 
Hippo pathway-independent restriction of TAZ and YAP by angiomotin.
Chan SW, Lim CJ, Chong YF, Pobbati AV, Huang C, Hong W.
J Biol Chem. 2011 Mar 4;286(9):7018-26. doi: 10.1074/jbc.C110.212621. Epub 2011 Jan 11.
PMID 21224387
 
The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells.
Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, Inui M, Montagner M, Parenti AR, Poletti A, Daidone MG, Dupont S, Basso G, Bicciato S, Piccolo S.
Cell. 2011 Nov 11;147(4):759-72. doi: 10.1016/j.cell.2011.09.048.
PMID 22078877
 
Role of YAP/TAZ in mechanotransduction.
Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S.
Nature. 2011 Jun 8;474(7350):179-83. doi: 10.1038/nature10137.
PMID 21654799
 
NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway.
Habbig S, Bartram MP, Muller RU, Schwarz R, Andriopoulos N, Chen S, Sagmuller JG, Hoehne M, Burst V, Liebau MC, Reinhardt HC, Benzing T, Schermer B.
J Cell Biol. 2011 May 16;193(4):633-42. doi: 10.1083/jcb.201009069. Epub 2011 May 9.
PMID 21555462
 
BMI-1 suppresses contact inhibition and stabilizes YAP in Ewing sarcoma.
Hsu JH, Lawlor ER.
Oncogene. 2011 Apr 28;30(17):2077-85. doi: 10.1038/onc.2010.571. Epub 2010 Dec 20.
PMID 21170084
 
E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components.
Kim NG, Koh E, Chen X, Gumbiner BM.
Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11930-5. doi: 10.1073/pnas.1103345108. Epub 2011 Jul 5.
PMID 21730131
 
Downregulation of SAV1 plays a role in pathogenesis of high-grade clear cell renal cell carcinoma.
Matsuura K, Nakada C, Mashio M, Narimatsu T, Yoshimoto T, Tanigawa M, Tsukamoto Y, Hijiya N, Takeuchi I, Nomura T, Sato F, Mimata H, Seto M, Moriyama M.
BMC Cancer. 2011 Dec 20;11:523. doi: 10.1186/1471-2407-11-523.
PMID 22185343
 
YAP is a candidate oncogene for esophageal squamous cell carcinoma.
Muramatsu T, Imoto I, Matsui T, Kozaki K, Haruki S, Sudol M, Shimada Y, Tsuda H, Kawano T, Inazawa J.
Carcinogenesis. 2011 Mar;32(3):389-98. doi: 10.1093/carcin/bgq254. Epub 2010 Nov 26.
PMID 21112960
 
Yap1 acts downstream of α-catenin to control epidermal proliferation.
Schlegelmilch K, Mohseni M, Kirak O, Pruszak J, Rodriguez JR, Zhou D, Kreger BT, Vasioukhin V, Avruch J, Brummelkamp TR, Camargo FD.
Cell. 2011 Mar 4;144(5):782-95. doi: 10.1016/j.cell.2011.02.031.
PMID 21376238
 
Hippo pathway regulation by cell morphology and stress fibers.
Wada K, Itoga K, Okano T, Yonemura S, Sasaki H.
Development. 2011 Sep;138(18):3907-14. doi: 10.1242/dev.070987. Epub 2011 Aug 10.
PMID 21831922
 
AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinoma.
Xu MZ, Chan SW, Liu AM, Wong KF, Fan ST, Chen J, Poon RT, Zender L, Lowe SW, Hong W, Luk JM.
Oncogene. 2011 Mar 10;30(10):1229-40. doi: 10.1038/onc.2010.504. Epub 2010 Nov 15.
PMID 21076472
 
The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene.
Zhang X, George J, Deb S, Degoutin JL, Takano EA, Fox SB; AOCS Study group, Bowtell DD, Harvey KF.
Oncogene. 2011 Jun 23;30(25):2810-22. doi: 10.1038/onc.2011.8. Epub 2011 Feb 14.
PMID 21317925
 
Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein.
Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q, Guan KL.
Genes Dev. 2011 Jan 1;25(1):51-63. doi: 10.1101/gad.2000111.
PMID 21205866
 
Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance.
Zhou D, Zhang Y, Wu H, Barry E, Yin Y, Lawrence E, Dawson D, Willis JE, Markowitz SD, Camargo FD, Avruch J.
Proc Natl Acad Sci U S A. 2011a Dec 6;108(49):E1312-20. doi: 10.1073/pnas.1110428108. Epub 2011 Oct 31.
PMID 22042863
 
TAZ is a novel oncogene in non-small cell lung cancer.
Zhou Z, Hao Y, Liu N, Raptis L, Tsao MS, Yang X.
Oncogene. 2011b May 5;30(18):2181-6. doi: 10.1038/onc.2010.606. Epub 2011 Jan 24.
PMID 21258416
 
Identification, basic characterization and evolutionary analysis of differentially spliced mRNA isoforms of human YAP1 gene.
Gaffney CJ, Oka T, Mazack V, Hilman D, Gat U, Muramatsu T, Inazawa J, Golden A, Carey DJ, Farooq A, Tromp G, Sudol M.
Gene. 2012 Nov 10;509(2):215-22. doi: 10.1016/j.gene.2012.08.025. Epub 2012 Aug 24.
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Written2014-05Federica Lo Sardo, Sabrina Strano, Giovanni Blandino
Oncogenomic Unit, Regina Elena Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy (FLS, GB); Molecular Chemoprevention Unit, Italian National Cancer Institute Regina Elena, 00144 Rome, Italy (SS)

Citation

This paper should be referenced as such :
Sardo F Lo, S Strano, G Blandino
The Hippo Kinase Pathway: a master regulator of proliferation, development and differentiation
Atlas Genet Cytogenet Oncol Haematol. 2015;19(1):65-77.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Deep/HippoKinasePathwayID20125.htm

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