BMB Reports 2018; 51(3): 106-118  https://doi.org/10.5483/BMBRep.2018.51.3.022
The history and regulatory mechanism of the Hippo pathway
Wantae Kim1,*, and Eek-hoon Jho2,*
1Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea, 2Departement of Life Science, University of Seoul, Seoul 02505, Korea
Correspondence to: Wantae Kim, Tel: +82-42-860-4385; Fax: +82-42-860-4489; E-mail: wantaekim@kribb.re.kr; Eek-hoon Jho, Tel: +82-2-6490-2671; Fax: +82-2-6490-2664; E-mail: ej70@uos.ac.kr
Received: January 8, 2018; Published online: March 31, 2018.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

How the organ size is adjusted to the proper size during development and how organs know that they reach the original size during regeneration remain long-standing questions. Based on studies using multiple model organisms and approaches for over 20 years, a consensus has been established that the Hippo pathway plays crucial roles in controlling organ size and maintaining tissue homeostasis. Given the significance of these processes, the dysregulation of the Hippo pathway has also implicated various diseases, such as tissue degeneration and cancer. By regulating the downstream transcriptional coactivators YAP and TAZ, the Hippo pathway coordinates cell proliferation and apoptosis in response to a variety of signals including cell contact inhibition, polarity, mechanical sensation and soluble factors. Since the core components and their functions of the Hippo pathway are evolutionarily conserved, this pathway serves as a global regulator of organ size control. Therefore, further investigation of the regulatory mechanisms will provide physiological insights to better understand tissue homeostasis. In this review, the historical developments and current understandings of the regulatory mechanism of Hippo signaling pathway are discussed.

Keywords: Development, Hippo pathway, Size control, TAZ, YAP
INTRODUCTION

Both the growth to the right size and the patterning to an accurate shape are essential for an organ to ensure functionality during development and regeneration. These have been obviously curious topics in biology; however, the mechanism for how organ size is controlled remains poorly understood (13). Organ size control is tightly coordinated in response to physiological cues that represent intrinsic and extrinsic mechanisms. In 1931, Twitty and Schwind provided the first clue that an organ possesses an intrinsic mechanism to determine its final size. When embryonic tissues that would become a leg were hetero-transplanted between two species of salamanders that have legs of different sizes, the legs grew to the final size of the donor (4). Likewise, a surgically removed liver regenerates quickly and stops growing when it reaches its original mass, which indicates that the intrinsic information of the organ, not the external signals, determines its final size (5). In this regard, how a growing organ can sense its current size and remember its original size to regulate its growth is still a mystery. Metcalf demonstrated a striking observation that organ size can be determined by both autonomous and non-autonomous mechanisms in mammalian systems. He demonstrated that each of the multiple thymus grafts to a recipient animal grew to an adult size, which supports an autonomous mechanism; while spleen grafts exhibited restricted growth capacity (6, 7). Collectively, these previous reports suggest that both intrinsic and extrinsic mechanisms operate in the regulation of organ size determination.

Organ growth is a consequence of an increase in cell number and/or cell size, which is affected by mitogen or growth factor-mediated signal transduction. Extensive studies using multiple approaches have identified that several signaling pathways, including Wnt/β-catenin, Notch and mTOR, are also involved in the regulation of cell size and/or number in metazoans. A growing body of evidence suggests that the Hippo pathway functions as a central regulator of organ size determination by coordinating cell proliferation and apoptosis. Components of the Hippo pathway and its growth-regulatory function are conserved in all metazoan animals as well as pre-metazoan origins (8, 9).

The Hippo pathway basically consists of a core kinase cascade containing the Ste-20 family of protein kinase MST1/2, the scaffolding protein Salvador, and large tumor suppressor kinase LATS1/2 to inhibit the transcriptional co-activators YAP and TAZ. A wide range of signals derived from cell contact, polarity, energy or mechanical stress and GPCR signaling activate the Hippo pathway, which eventually results in YAP/TAZ phosphorylation by LATS1/2 (1012). As a result, 14-3-3 interacts and induces the cytoplasmic retention of phosphorylated YAP/TAZ, which leads to β-TrCP-mediated proteasomal degradation (1315). However, the cytoskeleton rearrangement, genetic mutation or growth factors inhibit LATS1/2-mediated YAP/TAZ phosphorylation and enable YAP/TAZ to enter the nucleus to activate the transcriptional programs that are involved in cell proliferation and survival (12, 16). In addition, alternative models have shown that YAP/TAZ activity can be modulated by novel regulators such as deubiquitinase YOD1, MAP4 kinase or spatial organization of core components (1720). The Hippo pathway has a significant impact on a variety of human diseases including tissue degeneration and cancer. Besides the primary functions of cell proliferation and organ size control, the reports recently published expand our understanding of the Hippo pathway into previously unrecognized cellular processes including miRNA biogenesis, innate immunity, autophagy, atherogenesis, and cell ploidy (2129). Due to its importance in pathological and physiological contexts, the Hippo pathway has attracted much attention, and the numbers of reports are growing rapidly every year (Fig. 1).

LONG JOURNEY TO ELUCIDATION OF THE HIPPO PATHWAY

Discovery of the core components

In 1995, a mosaic-based screening in a Drosophila imaginal disc to identify genes involved in growth control revealed Warts (Wts), which encodes a kinase of the Nuclear Dbf2-related (NDR) family, as a tumor suppressor gene. The loss of Wts in flies resulted in robust overgrowth in multiple tissues without affecting cell fate determination (30, 31). The development of soft-tissue sarcomas and ovarian tumors in mice-deficient Lats1, a mammalian homologue of Drosophila Wts, further confirmed its tumor suppressive function in mammals (32). Although a cell cycle regulator CDC2 was identified as a binding partner (33), information regarding its regulators, substrates and additional binding partners remained largely unknown for several years since Wts was discovered. The identification of Salvador (Sav) by the two groups led to our interest in a novel growth-regulatory pathway (34, 35). Mutations in Sav, WW45 in humans, which contains two WW-domains, resulted in a similar overgrowth elicited by a mutation in Wts. In particular, Hariharan and colleagues have addressed the physical interaction of Sav with Wts and its function that limits cell proliferation and stimulate apoptosis by regulating Cyclin E and Diap (Drosophila inhibitor of apoptosis) transcriptionally. Supporting its role in tumor suppression, mutation in the human homologue WW45 was observed in cancer cell lines (34). The next substantial advance in the size-control mechanism was the discovery of the Hippo (Hpo) tumor suppressor gene, which encodes Ste-20 family protein kinase and is the homolog of MST1 and MST2 in humans (3640). Several independent groups have provided the evidence that Hpo genetically and physically interacts with Sav and Wts to restrict cell proliferation and function in a common pathway. Hpo-mediated phosphorylation of Sav and Wts is particularly significant because it provides the signaling module of a new growth-regulatory pathway (Hippo pathway) consisting of kinase cascade. Mats was incorporated as a bona fide regulator of the Hippo pathway. The loss-of-function of Mats causes massive tissue growth, which is similar to the phenotype caused by the loss of Hpo, Sav or Wts. Further investigation revealed that Mats, MOB1 in humans, phosphorylation by Hpo is required for Wts kinase activity (41, 42). Key findings on the Hippo signaling pathway are chronologically summarized in Fig. 2.

Yorkie/YAP as a transcriptional activator in the Hippo pathway

Since the expression of genes such as Cyclin E and Diap could be regulated by the Hippo pathway (36), the identification of the transcriptional regulator(s) that functionally link with upstream kinase cascade was required. In this regard, Huang et al. performed a yeast two hybrid screen with Wts as a bait to search for a transcriptional activator and finally identified Yorkie (Yki), YAP and its paralogue TAZ in mammals, as a downstream effector in growth regulation (10). Biochemical and genetic studies revealed that Yki is required for normal tissue growth and its activity is inhibited by Wts-mediated phosphorylation (10). In addition, the removal of Yki in Drosophila diminished the overgrowth phenotype caused by deleting upstream kinases Wts or Hpo, which indicated that Yki is a central transcription regulator of the Hippo signaling pathway. Guan and colleagues uncovered an underlying molecular mechanism by which Wts/LATS inhibits Yki/YAP activity. They observed YAP contains five LATS kinase consensus sequences (HxRxxS/T) and phosphorylation at S127 leads to cytoplasmic retention of YAP via the interaction with 14-3-3, thereby inhibiting transcriptional activity (43). The central mechanism of the Hippo signal transduction has been established by these remarkable findings and we are currently able to measure the output of the Hippo signaling by easily examining the level of phosphorylation on YAP-S127. In addition, the function of Yki as a critical effector in organ growth as demonstrated in flies was further confirmed in a genetic mouse model. The removal of Yap largely suppressed the phenotypes caused by the deletion of Nf2, a homolog of Drosophila Merlin that is an upstream regulator of Hpo (44). Therefore, growth regulatory function by Hpo-Yki/YAP signaling is evolutionarily conserved in the mechanism of size control. Expecting its growth-promoting capability, YAP was suggested as a potential oncogene due to its association with gene amplification and epigenetic modulation in human cancers, and it is currently accepted as a critical “driver” gene (4548). Taken together, the Hippo signaling plays a critical role in tumor suppression and its dysregulation is associated with human cancers. Further details about the role of Hippo signaling in different cancers are discussed in an accompanying paper (Kim and Myung, in this issue). The schematic diagram for the components of the Hippo signaling pathway described in this review is displayed in Fig. 3.

Role of Yki/YAP in transcriptional activation

Unlike other transcriptional factors, Yki and YAP/TAZ do not have a DNA-binding ability; therefore, they require binding partner(s) that directly bind to DNA and mediate target gene expression. YAP was identified by Sudol as the Yes, tyrosine kinase, -associated protein (49). Therefore, before elucidation of its crucial role in organ size control, several DNA binding proteins, including p73, p53BP-2, SMAD7, ERBB4, PEBP2α, RUNX2 and TEAD, had been already reported as YAP-interacting transcriptional factors (5056). The binding partners of YAP/TAZ are reviewed in detail in an accompanying paper (Kim et al., in this issue). However, the physiological relevance of these interactions in organ size control remains unknown. Multiple lines of evidence revealed that Scalloped (Sd), TEAD1–4 in humans, is the major binding partner of Yki/Yap in regulating gene expression and tissue growth (5760). The loss of TEAD as well as the TEAD-binding deficient mutant of YAP (S94A or S79A in humans or mice, respectively) can no longer activate target gene expression. Additionally, the knock-in (KI) of this TEAD binding mutant exhibits a similar phenotype as the YAP knockout (KO) in mice tissues (61, 62). The list of the genes induced by YAP generally overlapped with that activated by TEAD or TEAD-VP16 (YAP-binding deficient but a constitutively active form of TEAD via a fusion of VP16 transactivation domain) (57, 60). Recent studies suggested that VGLL4 competes with YAP for binding TEAD and functions as a tumor suppressor (63). Tgi, a similarly functioning protein like VGLL4, was also observed in Drosophila (64). It is not known how YAP/TAZ is translocated into the nucleus and will be interesting to test whether those YAP/TAZ interacting partners are involved in that process.

UPSTREAM SIGNALS OF THE HIPPO PATHWAY

Cell polarity and cell contact

The growth-regulatory pathway from MST1/2 (Hpo) to YAP/TAZ (Yki)-mediated transcription was established almost a decade after the first gene, Wts, was identified. However, it remains questionable which and how the physiological cues were delivered into the Hippo pathway in regulating organ size. The identification of the apical-basal and planar cell polarity machinery that regulate Hippo signaling initially provided the entry point to understanding these missing links. The FERM domain proteins Merlin (Mer) and Expanded (Ex) have known to co-localize at the adherens junctions to link transmembrane proteins to the cytoskeleton. In addition, the mutation in the Neurofibromatosis type-2 (Nf2), a homolog of Drosophila Merlin, causes a familial cancer syndrome; but, its downstream mechanism remains elusive. Hamaratoglu et al. clearly demonstrated that Mer and Ex genetically function at the upstream of Hpo kinase and as tumor suppressors (65). Mer and Ex synergistically induce Wts phosphorylation and subsequent Yki inhibition. Moreover, it soon became apparent that atypical cadherin Fat could act at the upstream of Ex by promoting its stability and apical membrane localization (6668). Also, the Sterile 20-like kinase Tao-1 has been reported as a mediator that connects upstream components Ex and Mer to the Hippo pathway by directly phosphorylating and activating Hpo kinase, which leads to a Wts mediated repression of Yki (69, 70). Recently, it has been reported that Ex is required for apical localization of Schwannomin interacting protein 1 (Schip1) and Schip1 recruits Tao-1 kinase for the phosphorylation of Hpo kinase (71). Another major progress was made by the identification of Kibra (7274). Kibra forms a complex with Ex and Mer to recruit the core components to the apical junction in the epithelial cell for Hippo signaling activation. Su et al. have further added another mode of regulation which shows that Kibra activates the Hippo pathway together with Mer and Sav, but independent of Ex, at the non-junctional site (medial apical cortex) (75). Crumbs (Crb) was identified as a putative surface receptor linking apical polarity with organ size determination. Interestingly, both overexpression and depletion of Crb, induces Yki activity, thereby driving tissue overgrowth; although, it has been reported as a tumor suppressor in human cancer (7679). In addition to the apical component such as Ex, components of Crb polarity complex, including PALS1, PATJ and AMOT, are also able to strongly interact and induce cytoplasmic retention of YAP/TAZ when cells are in high density (80). These remarkable findings have established cell polarity as an intrinsic upstream signal of the Hippo pathway in controlling organ size and tumorigenesis.

Cell-adhesion molecules are regulators of the Hippo pathway and function as tumor suppressors. α-catenin, an adaptor protein between the membrane and actin cytoskeleton for adherens junction (AJ) formation, was discovered as a molecular linker between the AJ and Hippo pathway (81, 82). Through molecular and genetic analysis of the mouse model, it was reported that α-catenin functions as a tumor suppressor in skin epidermis by preventing nuclear localization and transcriptional activity of YAP (61, 83). A component of cell adhesion junction Echinoid was also identified as a tumor suppressor and upstream modulator of the Hippo pathway. Echinoid physically interacts with and stabilizes Sav, thereby inactivating the Yki activity in Drosophila (84, 85). Thus, cell junction formation exerts as an intrinsic cue to regulate the Hippo signaling. A detailed discussion on the upstream paths for Hippo signaling in Drosophila organ development is reviewed in an accompanying paper (Choi, in this issue).

Physical signals

Cells are exposed to physical constraints or mechanical cues during organ growth and regeneration and then activate the Hippo pathway to limit tissue overgrowth by restricting cell proliferation and survival. Cell contact inhibition is a well-established growth-inhibitory signal and acts as a determinant of YAP inactivation in the cell culture system as well as in vivo. At high cell density, LATS1/2 kinase are activated and phosphorylates YAP and TAZ at S127 and S89, respectively, which generate a docking site for the 14-3-3 interaction. 14-3-3 retains YAP/TAZ at the cytoplasm and consequently induces their degradation via the β-TrCP E3 ligase-mediated ubiquitin proteasome system. The levels of many Hippo signaling components are controlled by ubiquitin modification. Further discussion on the role of ubiquitin modification in diverse cellular contexts is described in an accompanying paper (Kim and Jho, in this issue). On the other hand, YAP is predominantly present in the nucleus at low cell density, when LATS1/2 kinase activity is low. A physiological relevance to cell density-dependent YAP regulation was further elucidated in the early fate decision of trophectoderm and inner cell mass in mice embryos. YAP primarily localizes in the nuclei of outer cells, where cells are not fully enclosed by other cells, and it mimics low cell density. Whereas, YAP is phosphorylated and present in the cytoplasm of inner cells that are surrounded by other cells which mimics high cell density. The differential localization patterns of YAP between the inner and outer cells is crucial for cell fate determination (57, 86). In addition to LATS1/2 kinase, the non-receptor tyrosine phosphatase PTPN14 has emerged as a cell-density dependent regulator of YAP regardless of its enzymatic activity. The direct interaction of PTPN14 with YAP promotes the cytoplasmic sequestration of YAP from the nucleus in response to cell contact inhibition (8789). More recently, Nemo-like kinase (NLK) regulates YAP localization and transcriptional activity in a cell-density dependent manner. At low cell density, NLK directly phosphorylates YAP at S128, which blocks LATS1/2-mediated phosphorylation at S127 and the 14-3-3 interaction. However, NLK is unable to activate YAP at a high cell density due to its cytoplasmic localization and degradation (90).

Many types of mechanical signals, including fluid shear stress, cell geometry and tensional force, have an effect on the complex architectures of organs and a growing body of evidence has placed YAP/TAZ as the critical mechanosensitive transducers that translate mechanical inputs into gene expression (9193). These roles of YAP/TAZ in mechanotransduction are important in the physiological and pathological relevance to better understand related diseases, including atherosclerosis and cardiac hypertrophy, and mesenchymal stem cell differentiation (93). Physical alteration by ECM stiffness and cell shape regulates YAP/TAZ nuclear localization via the cytoskeleton rearrangement which is determined by Rho-GTPase, FAK-Src or LATS1/2 dependent pathways (94, 95). Recent report suggests that extracellular stiffness applied from the cytoskeleton into the nucleus can stretch the nuclear pore and consequently increase the nuclear entry of YAP (96). Further details about the regulation of Hippo signaling by actin remodeling are reviewed in an accompanying paper (Seo and Kim, in this issue).

Cellular stress

Because YAP/TAZ are multifunctional transcription activators involved in a variety of cellular responses and a tight coordination between metabolism and the signaling pathway involved in cell proliferation is eventually required for organ growth, it has been expected that several stress signals such as nutrient starvation, energy stress and hypoxia may have effect on the Hippo signaling pathway (11, 97). The first link of YAP/TAZ to cellular metabolism emerged from the mevalonate pathway that has crucial roles in multiple cellular processes by synthesizing essential bioactive molecules such as cholesterol, bile acid and dolichol (98, 99). Pharmacological inhibitors of the mevalonate pathway efficiently block YAP/TAZ activity though RHO-GTPase (99). Serum or glucose deprivation rapidly induces LATS1/2 activation and subsequent YAP/TAZ inactivation for energy homeostasis. Moreover, the kinase AMPK, as a sensor of cellular energy stress, directly phosphorylates YAP at S94, which is a residue essential for the interaction with TEAD, to disrupt the interaction with TEAD (100, 101). Recent reports further provided interesting finding that YAP is O-GlcNAcylated by OGT in response to metabolic nutrients. YAP O-GlcNAcylation inhibits LATS1 mediated phosphorylation of YAP and represses YAP activity in tumorigenesis (102, 103).

Hypoxia represents a low level of oxygen at the tissue level and is a common feature in a majority of malignant tumors. HIF-1α functions as an oxygen sensor and is highly increased under hypoxia. Recent reports suggest that hypoxic stress deactivates the Hippo pathway via SIAH2-meidated LATS1/2 degradation. Augmented YAP interacts with HIF-1α which enhances YAP stabilization and function in tumors (104). Likewise, HIF-2α promotes cancer cell growth by inducing YAP expression and activity (105). In addition to YAP, HIF-1α can activate the WWTR gene that encodes the TAZ protein and serves as a co-activator (106). Further investigation provided details regarding the molecular mechanism for SIAH2-mediated LATS degradation under hypoxia. TGF-β signaling and expression of its target gene Zyxin are significantly elevated under hypoxia. As a result, Zyxin forms a functional ternary complex with LATS2 and SIAH2 and facilitates LATS2 degradation (107). Osmotic stress is recently reported to modulate the Hippo signaling; although, temporal duration exposed to osmotic stress differently affects YAP activity (108, 109). Acute osmotic stress promotes YAP nuclear localization and transcriptional activity by NLK-mediated phosphorylation (108). However, at later stages, osmotic stress promotes cytoplasmic translocation of TEAD via direct interaction with p38, which leads to the inhibition of YAP activity (109).

MST1/2 is originally isolated as a stress-responsive kinase activated by extreme stress, such as heat shock, okadaic acid or sodium arsenite (110), and mediates cellular responses to oxidative stress and longevity through the FOXO transcriptional factor (111). Recent work revealed that the YAP directly forms a functional complex with FOXO1 to activate the expression of antioxidant genes and consequently exert protective effects against oxidative stress and ischemia/reperfusion (I/R)-caused injury in the heart (112). Further identification and functional analysis of new players that link stress and nutrients to Hippo signaling will provide potential therapeutic intervention points for treating cancer and metabolic diseases.

HIPPO PATHWAY IS A HUB FOR INTEGRATION OF OTHER SIGNALING PATHWAYS

Multiple signaling pathways converge and integrate with other pathways in tightly regulating numerous cellular responses, development and pathogenesis. In this review, we discuss the cross-talks between Hippo and other signaling pathways such as Wnt, Notch, GPCR and TGFβ pathways (Fig. 3).

Wnt/β-catenin signaling pathway

The Wnt/β-catenin pathway is known for its crucial role in embryonic development and tissue homeostasis in adults (113). In the absence of Wnt stimulation, a key transcriptional activator β-catenin is constantly degraded by a destruction complex that includes Axin, APC and GSK-3β, thereby maintaining a low level of β-catenin in the cytoplasm. Conversely, cytoplasmic β-catenin is accumulated in the presence of Wnt stimulation and enters the nucleus to activate the Wnt-responsive transcriptional program (113, 114). Multiple studies suggested that the Hippo pathway and Wnt/β-catenin signaling are integrated for the fine regulation of its own signaling in a physiological context. The first evidence for crosstalk between the Hippo and Wnt/β-catenin pathway was provided by Attisano and colleagues (115). The activation of the Hippo pathway increases the level of cytoplasmic TAZ to repress Wnt/β-catenin signaling by inhibiting CK1δ/ɛ-mediated phosphorylation of Dishevelled (DVL). The Taz-KO mouse is known to develop a severe polycystic kidney (PKD) that is similar to the phenotype caused by aberrant Wnt/β-catenin signaling activation and it exhibits elevated transcriptional activity of β-catenin in kidney cysts. Interestingly, the levels of Armadillo, β-catenin homolog in Drosophila, and expression of its target genes are increased in the hpo and wts mutant clone of Drosophila (115). Similarly, YAP/TAZ physically binds and sequestrates β-catenin in the cytoplasm, thereby suppressing Wnt signaling (116). Furthermore, cytoplasmic YAP displayed a tumor suppressive function by restricting the nuclear translocation of DVL without modulating Axin-APC-GSK3β complex, and subsequently dampening Wnt signaling activation during intestinal regeneration (117). Alternatively, the Hippo pathway regulates the subcellular distribution of SHP2 tyrosine phosphatase that is known to be a potent activator of Wnt/β-catenin signaling at the nucleus in a cell-density dependent manner. In high cell density, SHP2 is cytoplasmic via an interaction with phosphorylated YAP/TAZ, which suggests that the activation of Hippo signaling suppresses the Wnt signaling activity. Conversely, un-phosphorylated YAP/TAZ promotes SHP2 nuclear localization and ultimately activates Wnt signaling in low cell density (118). Taken together, there are at least four different ways that the Hippo signaling inhibits Wnt/β-catenin signaling and the main mechanism is sequestration of the activators of Wnt/β-catenin signaling in the cytoplasm by interacting with cytoplasmic YAP/TAZ.

It is likely that the in vivo reciprocal relationship between Wnt/β-catenin and the Hippo pathway depends on the tissue context. Deletion of the Hippo components, Sav and Mst1/2, in neonatal heart displayed induced cardiomyocyte proliferation and cardiomegaly together with the elevated Wnt/β-catenin signaling signature (119). YAP and β-catenin forms a complex in the promoter of the progenitor genes, such as Sox2 and Snai2/Slug, and enhances gene expression. Heterozygotic removal of β-catenin in Sav-KO suppressed cardiomyocyte proliferation and heart overgrowth, which suggests that Wnt/β-catenin signaling is required for the phenotypes in Hippo mutants (119). Likewise, the ablation of the Hippo signaling by genetically deleting Mst1 and Mst2 (Mst1/2-DKO) resulted in the elevation of YAP/TAZ as well as β-catenin signaling activity. However, in contrast to its effect on the heart, additional loss of β-catenin in the Mst1/2-DKO mouse livers caused very severe hepatomegaly and accelerated tumor formation than those observed in Mst1/2-DKO (120). In line with this, the clinical investigation reveals that the YAP activation signature exhibits a negative correlation with β-catenin activation signature in patients with hepatocellular carcinoma (121). These reports suggest that YAP/TAZ can act as oncogene or tumor suppressor in a context dependent manner.

A large body of evidence has suggested that YAP/TAZ are intrinsic regulators of Wnt signal transduction and orchestrates Wnt-mediated biological responses. Similar to the β-catenin regulation, YAP and TAZ were integral components and sequestrated by the β-catenin destruction complex in the cytoplasm. β-catenin mediates TAZ, but not YAP, degradation in the absence of Wnt. YAP/TAZ also inhibit β-catenin activity via the recruitment of β-TrCP into the destruction complex. However, in the presence of Wnt, YAP and TAZ are released from the destruction complex and enter into the nucleus to enhance target gene expression (122, 123). These provocative findings suggest that the expression of Wnt target genes is regulated by the well-known β-catenin-TCF/LEF as well as YAP/TAZ-TEAD complexes. However, Pan and colleagues demonstrated that YAP is not regulated by the β-catenin destruction complex, but rather the APC protein complex that facilitates the phosphorylation of YAP/TAZ through the Hippo kinase cascade (124). It is not clear whether this discrepancy is due to difference in the cellular context. Further work is required to resolve this discrepancy.

G-protein-coupled receptors (GPCRs)

G-protein-coupled receptors (GPCRs) contain seven transmembrane domains and are the largest family of the plasma membrane receptors that mediate signals from the outside to the inside of the cell. A major conceptual advance was the identification of GPCRs as a bona fide upstream regulator of the Hippo signaling pathway (125). GPCR signaling differentially regulates the Hippo pathway, which depends on the types of heterotrimeric G-protein that are induced by the different ligands. Guan and colleagues examined the effect of serum on YAP/TAZ phosphorylation and activation to search for upstream regulators of the Hippo pathway. Serum induces the dephosphorylation and nuclear translocation of YAP, and further investigation identified bioactive phospholipids in serum, such as lysophosphatidic acid (LPA) or sphingosine 1-phosphate (S1P), as the YAP/TAZ activating components. LPA or S1P treatment was sufficient to promote YAP/TAZ activation through G12/13-coupled receptor signaling. Further investigation indicated GPCRs that activate G12/13, Gq/11 and Gi/o signaling inhibit YAP/TAZ phosphorylation and degradation. In particular, the YAP/TAZ regulation by GPCR is closely associated with a variety of cancers. For example, Gq/11-active mutation is observed in approximately 80% of uveal melanoma where YAP has the essential role in tumorigenesis. Mechanistically, these GPCRs inhibit LATS1/2 activity through Rho-GTPase, thereby inducing YAP/TAZ dephosphorylation and nuclear localization. In contrast, ephinephrine, glucagon or dopamine that activates Gs-coupled receptor elevated LATS1/2 kinase activity through protein kinase A and consequently inhibits YAP/TAZ activity. LATS1/2 served as the key downstream mediators in the regulation of YAP/TAZ by GPCRs; but, it remains controversial since Miller et al. demonstrated that LATS1/2 was not involved in S1P-mediated YAP dephosphorylation (126). Frizzled (Fz) is a primary receptor for Wnt ligands and belongs to the GPCR family. A recent study reported that the noncanonical Wnt ligands, such as Wnt5a/b, activate YAP/TAZ via Fz-G12/13-RhoGTPase-LATS1/2 signaling axis that is independent from the canonical Wnt/β-catenin pathway (127). It would be of importance to identify more GPCRs which transduce the extracellular signal to the Hippo signaling pathway in different cellular contexts, since these GPCRs can be used as specific therapeutic targets by using currently available agonists or antagonists.

Notch signaling pathway

Notch signaling functions in diverse developmental and homeostatic processes and is activated by cell-cell contact that induce the direct interaction between the Notch receptors and their cognate ligands (Jagged and Delta-like). These bindings induce sequential proteolytic cleavage of the Notch receptor and ultimately generate the Notch intracellular domain (NICD) to activate the expression of target genes (128130). Although the Hippo pathway was initially reported to be involved in the Notch-dependent differentiation in Drosophila (131, 132), a direct link between the two signaling pathways was extensively studied in mammalian development and tissue homeostasis. Genetic manipulation revealed that YAP was required for intestinal expansion, smooth muscle differentiation and controlling liver cell fate via the up-regulation of the Notch signaling (133136). During embryonic development, the Notch pathway is activated in the trophoectoderm (TE), which give rise to the placenta, where NICD and YAP cooperatively activate Cdx2 transcription for TE lineage specification (137). A series of studies provided the mechanistic insight that Notch receptors and its ligand Jagged1 were direct target genes of YAP and NICD enhanced YAP/TAZ activity by at least promoting stabilization, which creates a positive feedback loop during tumorigenesis (120, 134, 138).

TGF-β signaling

The transforming growth factor-β (TGF-β) superfamily participates in the regulation of numerous biological processes, including cell growth, organogenesis and stem cell function (139). The TGFβ ligands bind to their specific Ser/Thr kinase receptors to induce the activation of SMAD transcription factors and its target gene expression. Recent studies have unveiled a cooperative interaction between the Hippo and TGFβ-SMAD signaling in many cellular responses (140142). In human embryonic stem cells (hESC), the Hippo pathway cooperates with the TGFβ signaling to maintain pluripotency (143). Upon TGFβ stimulation, TAZ physically binds and promotes SMAD2/3 nuclear localization to induce the transcription of genes that are involved in the maintenance of hESC pluripotency (143). Conversely, in response to cell density, the Hippo pathway suppresses the TGFβ signaling via YAP/TAZ-mediated SMAD cytoplasmic sequestration (80). However, YAP/TAZ-dependent SMAD localization needs to be further clarified since the controversial result was reported that the TGFβ signaling and SMAD nuclear localization was not affected by cell density in most cell types (144). In addition to its role in embryonic stem cells, YAP controls patterning of the developing lung and induces specific transcriptional programs to generate airways (145, 146). YAP also induces the differentiation of hepatoblasts into biliary epithelial cells by cooperating with the TGFβ signaling (147). YAP/TAZ and TGFβ signaling can form a positive feedback loop in tumorigenesis. TGFβ ligands, including BMP and TGFβ2/3, can be transcriptionally induced by the inactivation of the Hippo pathway (148, 149). A specific loss of Mob1a/b, which is a negative regulator of YAP/TAZ, in the liver results in the increase of Tgfβ2/3 expression. Indeed, the genetic ablation of the Tgfβ receptor (Tgfbr2) in Mob1a/b-deficient mice livers partially alleviated liver enlargement, fibrosis and tumorigenesis (149).

Multiple molecular layers between the Hippo pathway and TGFβ signaling have been reported. The Hippo pathway scaffold RASFF1A was degraded by the ITCH E3 ligase mediated proteasome pathway in response to TGFβ signaling, thereby permitting the YAP-SMAD2 complex formation and nuclear localization for transcriptional activation of the TGFβ-responsive targets (150). SnoN, which is a target gene of TGFβ signaling and maintains the repressed state of TGFβ-responsive targets in the absence of ligands as a negative feedback mechanism (151), promotes TAZ stabilization via the inhibition of LATS-mediated phosphorylation and is required for oncogenic function of TAZ (147). Interestingly, the expression and localization of SnoN can be regulated by cell density-dependent Hippo pathway activation (152). Overall, those reports clearly suggest that there are extensive cross-talks between the components of the Hippo and TGFβ signaling, and thus we need to be aware that modulation of one signaling may have elicit unexpected effects by regulating any other signaling.

CONCLUDING REMARKS

Owing to vast efforts of many researchers, the Hippo pathway has been firmly established as a master regulator of organ size control. Also, the molecular mechanism of the Hippo pathway that transduces from the extracellular stimuli to transcription has been well elucidated. Apart from its primary functions in organ size determination, development and tumor suppression, recent studies revealed the unexpected roles of Hippo signaling in diverse cellular processes such as angiogenesis (Park and Kwon, in this issue), miRNA biogenesis, regulation of innate immunity and mechanotransduction. Given these various cellular functions, it is not surprising that the Hippo pathway senses multiple stimuli and translates it to intracellular responses by cooperating with other signaling pathways. Despite the rapid and extensive progress in the Hippo pathway, further provocative findings are expected in coming years to answer fundamental questions in this field and to provide clinical insights for curing human diseases.

ACKNOWLEDGEMENTS

We sincerely apologize to researchers whose work is not cited in this review due to space limitations. This work was supported by the grants from the KRIBB Initiative of the Korea Research Council of Fundamental Science and Technology to W. Kim and the National Research Foundation of Korea (NRF-2016R1E1A1A01943544 and NRF-2017M3A9B4062421) to E. Jho.

CONFLICTS OF INTEREST

The authors have no conflicting interests.

Figures
Fig. 1. The pathophysiological function and importance of the Hippo pathway. Both intrinsic and extrinsic signals regulate the Hippo pathway that is crucial for proper developmental processes and tissue homeostasis (upper panel). As the interest and importance of the Hippo pathway is growing, so does the number of publications (bottom panel).
Fig. 2. Timeline of the major advances and discoveries in the Hippo pathway.
Fig. 3. Schematic model of the Hippo pathway and cross-talk with other signaling pathways in mammals. The Hippo pathway is a kinase cascade that consists of MST1/2-LATS1/2 and can be activated by diverse stimuli including cell density, polarity and mechanical cues to suppress YAP/TAZ transcriptional activity. Many modulators in the Hippo pathway have been added via multiple approaches (left panel). The crosstalk of the Hippo pathway with other signaling pathways such as Wnt/β-catenin, Notch and TGF-β to regulate YAP/TAZ activity (right panel).
References
  1. Shingleton, AW (2010). The regulation of organ size in Drosophila: physiology, plasticity, patterning and physical force. Organogenesis. 6, 76-87.
    Pubmed KoreaMed CrossRef
  2. Gokhale, RH, and Shingleton, AW (2015). Size control: the developmental physiology of body and organ size regulation. Wiley Interdiscip Rev Dev Biol. 4, 335-356.
    Pubmed CrossRef
  3. Halder, G, and Johnson, RL (2011). Hippo signaling: growth control and beyond. Development. 138, 9-22.
    KoreaMed CrossRef
  4. Twitty, VCS, and Josep, L (1931). The growth of eyes and limbs transplanted heteroplastically between two species of Amblystoma. J Exp Zool. 59, 61-86.
    CrossRef
  5. Michalopoulos, GK, and DeFrances, MC (1997). Liver regeneration. Science. 276, 60-66.
    Pubmed CrossRef
  6. Metcalf, D (1964). Restricted Growth Capacity of Multiple Spleen Grafts. Transplantation. 2, 387-392.
    Pubmed CrossRef
  7. Metcalf, D (1963). The Autonomous Behaviour of Normal Thymus Grafts. Aust J Exp Biol Med Sci. 41, 437-447.
    CrossRef
  8. Hilman, D, and Gat, U (2011). The evolutionary history of YAP and the hippo/YAP pathway. Mol Biol Evol. 28, 2403-2417.
    Pubmed CrossRef
  9. Sebe-Pedros, A, Zheng, Y, Ruiz-Trillo, I, and Pan, D (2012). Premetazoan origin of the hippo signaling pathway. Cell Rep. 1, 13-20.
    Pubmed KoreaMed CrossRef
  10. Huang, J, Wu, S, Barrera, J, Matthews, K, and Pan, D (2005). The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell. 122, 421-434.
    Pubmed CrossRef
  11. Meng, Z, Moroishi, T, and Guan, KL (2016). Mechanisms of Hippo pathway regulation. Genes Dev. 30, 1-17.
    Pubmed KoreaMed CrossRef
  12. Piccolo, S, Dupont, S, and Cordenonsi, M (2014). The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev. 94, 1287-1312.
    Pubmed CrossRef
  13. Zhao, B, Li, L, Tumaneng, K, Wang, CY, and Guan, KL (2010). A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev. 24, 72-85.
    Pubmed KoreaMed CrossRef
  14. Liu, CY, Zha, ZY, and Zhou, X (2010). The hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCF{beta}-TrCP E3 ligase. J Biol Chem. 285, 37159-37169.
    Pubmed KoreaMed CrossRef
  15. Huang, W, Lv, X, and Liu, C (2012). The N-terminal phosphodegron targets TAZ/WWTR1 protein for SCFbeta-TrCP-dependent degradation in response to phosphatidylinositol 3-kinase inhibition. J Biol Chem. 287, 26245-26253.
    Pubmed KoreaMed CrossRef
  16. Hansen, CG, Moroishi, T, and Guan, KL (2015). YAP and TAZ: a nexus for Hippo signaling and beyond. Trends Cell Biol. 25, 499-513.
    Pubmed KoreaMed CrossRef
  17. Meng, Z, Moroishi, T, and Mottier-Pavie, V (2015). MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Nat Commun. 6, 8357.
    Pubmed KoreaMed CrossRef
  18. Kim, Y, Kim, W, and Song, Y (2017). Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability. Proc Natl Acad Sci U S A. 114, 4691-4696.
    Pubmed KoreaMed CrossRef
  19. Yin, F, Yu, J, Zheng, Y, Chen, Q, Zhang, N, and Pan, D (2013). Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell. 154, 1342-1355.
    Pubmed KoreaMed CrossRef
  20. Fulford, A, Tapon, N, and Ribeiro, PS (2017). Upstairs, downstairs: spatial regulation of Hippo signalling. Curr Opin Cell Biol. 51, 22-32.
    Pubmed CrossRef
  21. Chaulk, SG, Lattanzi, VJ, Hiemer, SE, Fahlman, RP, and Varelas, X (2014). The Hippo pathway effectors TAZ/YAP regulate dicer expression and microRNA biogenesis through Let-7. J Biol Chem. 289, 1886-1891.
    KoreaMed CrossRef
  22. Mori, M, Triboulet, R, and Mohseni, M (2014). Hippo signaling regulates microprocessor and links cell-density-dependent miRNA biogenesis to cancer. Cell. 156, 893-906.
    Pubmed KoreaMed CrossRef
  23. Sabine, A, Bovay, E, and Demir, CS (2015). FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature. J Clin Invest. 125, 3861-3877.
    Pubmed KoreaMed CrossRef
  24. Wang, L, Luo, JY, and Li, B (2016). Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature. 540, 579-582.
    CrossRef
  25. Liu, B, Zheng, Y, Yin, F, Yu, J, Silverman, N, and Pan, D (2016). Toll Receptor-Mediated Hippo Signaling Controls Innate Immunity in Drosophila. Cell. 164, 406-419.
    Pubmed KoreaMed CrossRef
  26. Wang, S, Xie, F, and Chu, F (2017). YAP antagonizes innate antiviral immunity and is targeted for lysosomal degradation through IKKvarepsilon-mediated phosphorylation. Nat Immunol. 18, 733-743.
    Pubmed CrossRef
  27. Wilkinson, DS, Jariwala, JS, and Anderson, E (2015). Phosphorylation of LC3 by the Hippo kinases STK3/STK4 is essential for autophagy. Mol Cell. 57, 55-68.
    KoreaMed CrossRef
  28. Maejima, Y, Kyoi, S, and Zhai, P (2013). Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2. Nat Med. 19, 1478-1488.
    Pubmed KoreaMed CrossRef
  29. Zhang, S, Chen, Q, and Liu, Q (2017). Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2. Cancer Cell. 31, 669-684 e7.
    Pubmed KoreaMed CrossRef
  30. Justice, RW, Zilian, O, Woods, DF, Noll, M, and Bryant, PJ (1995). The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev. 9, 534-546.
    Pubmed CrossRef
  31. Xu, T, Wang, W, Zhang, S, Stewart, RA, and Yu, W (1995). Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development. 121, 1053-1063.
    Pubmed
  32. St John, MA, Tao, W, and Fei, X (1999). Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nat Genet. 21, 182-186.
    Pubmed CrossRef
  33. Tao, W, Zhang, S, and Turenchalk, GS (1999). Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nat Genet. 21, 177-181.
    Pubmed CrossRef
  34. Tapon, N, Harvey, KF, and Bell, DW (2002). salvador Promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell. 110, 467-478.
    Pubmed CrossRef
  35. Kango-Singh, M, Nolo, R, and Tao, C (2002). Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development. 129, 5719-5730.
    Pubmed CrossRef
  36. Harvey, KF, Pfleger, CM, and Hariharan, IK (2003). The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell. 114, 457-467.
    Pubmed CrossRef
  37. Udan, RS, Kango-Singh, M, Nolo, R, Tao, C, and Halder, G (2003). Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat Cell Biol. 5, 914-920.
    Pubmed CrossRef
  38. Pantalacci, S, Tapon, N, and Leopold, P (2003). The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol. 5, 921-927.
    Pubmed CrossRef
  39. Jia, J, Zhang, W, Wang, B, Trinko, R, and Jiang, J (2003). The Drosophila Ste20 family kinase dMST functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis. Genes Dev. 17, 2514-2519.
    Pubmed KoreaMed CrossRef
  40. Wu, S, Huang, J, Dong, J, and Pan, D (2003). hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell. 114, 445-456.
    Pubmed CrossRef
  41. Lai, ZC, Wei, X, and Shimizu, T (2005). Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. Cell. 120, 675-685.
    Pubmed CrossRef
  42. Wei, X, Shimizu, T, and Lai, ZC (2007). Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila. EMBO J. 26, 1772-1781.
    Pubmed KoreaMed CrossRef
  43. Zhao, B, Wei, X, and Li, W (2007). Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21, 2747-2761.
    Pubmed KoreaMed CrossRef
  44. Zhang, N, Bai, H, and David, KK (2010). The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell. 19, 27-38.
    Pubmed KoreaMed CrossRef
  45. Overholtzer, M, Zhang, J, and Smolen, GA (2006). Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci U S A. 103, 12405-12410.
    Pubmed KoreaMed CrossRef
  46. Harvey, KF, Zhang, X, and Thomas, DM (2013). The Hippo pathway and human cancer. Nat Rev Cancer. 13, 246-257.
    Pubmed CrossRef
  47. Johnson, R, and Halder, G (2014). The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat Rev Drug Discov. 13, 63-79.
    KoreaMed CrossRef
  48. Moroishi, T, Hansen, CG, and Guan, KL (2015). The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer. 15, 73-79.
    Pubmed KoreaMed CrossRef
  49. Sudol, M (1994). Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. Oncogene. 9, 2145-2152.
    Pubmed
  50. Komuro, A, Nagai, M, Navin, NE, and Sudol, M (2003). WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J Biol Chem. 278, 33334-33341.
    Pubmed CrossRef
  51. Ferrigno, O, Lallemand, F, and Verrecchia, F (2002). Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling. Oncogene. 21, 4879-4884.
    Pubmed CrossRef
  52. Strano, S, Munarriz, E, and Rossi, M (2001). Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J Biol Chem. 276, 15164-15173.
    Pubmed CrossRef
  53. Zaidi, SK, Sullivan, AJ, and Medina, R (2004). Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription. EMBO J. 23, 790-799.
    Pubmed KoreaMed CrossRef
  54. Vassilev, A, Kaneko, KJ, Shu, H, Zhao, Y, and DePamphilis, ML (2001). TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm. Genes Dev. 15, 1229-1241.
    Pubmed KoreaMed CrossRef
  55. Yagi, R, Chen, LF, Shigesada, K, Murakami, Y, and Ito, Y (1999). A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J. 18, 2551-2562.
    Pubmed KoreaMed CrossRef
  56. Espanel, X, and Sudol, M (2001). Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains. J Biol Chem. 276, 14514-14523.
    Pubmed CrossRef
  57. Ota, M, and Sasaki, H (2008). Mammalian Tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of Hippo signaling. Development. 135, 4059-4069.
    Pubmed CrossRef
  58. Wu, S, Liu, Y, Zheng, Y, Dong, J, and Pan, D (2008). The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev Cell. 14, 388-398.
    Pubmed CrossRef
  59. Zhang, L, Ren, F, Zhang, Q, Chen, Y, Wang, B, and Jiang, J (2008). The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. Dev Cell. 14, 377-387.
    Pubmed KoreaMed CrossRef
  60. Zhao, B, Ye, X, and Yu, J (2008). TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 22, 1962-1971.
    Pubmed KoreaMed CrossRef
  61. Schlegelmilch, K, Mohseni, M, and Kirak, O (2011). Yap1 acts downstream of alpha-catenin to control epidermal proliferation. Cell. 144, 782-795.
    Pubmed KoreaMed CrossRef
  62. von Gise, A, Lin, Z, and Schlegelmilch, K (2012). YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. Proc Natl Acad Sci U S A. 109, 2394-2399.
    Pubmed KoreaMed CrossRef
  63. Zhang, W, Gao, Y, and Li, P (2014). VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex. Cell Res. 24, 331-343.
    Pubmed KoreaMed CrossRef
  64. Koontz, LM, Liu-Chittenden, Y, and Yin, F (2013). The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression. Dev Cell. 25, 388-401.
    Pubmed KoreaMed CrossRef
  65. Hamaratoglu, F, Willecke, M, and Kango-Singh, M (2006). The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol. 8, 27-36.
    CrossRef
  66. Willecke, M, Hamaratoglu, F, and Kango-Singh, M (2006). The fat cadherin acts through the hippo tumor-suppressor pathway to regulate tissue size. Curr Biol. 16, 2090-2100.
    Pubmed CrossRef
  67. Silva, E, Tsatskis, Y, Gardano, L, Tapon, N, and McNeill, H (2006). The tumor-suppressor gene fat controls tissue growth upstream of expanded in the hippo signaling pathway. Curr Biol. 16, 2081-2089.
    Pubmed CrossRef
  68. Cho, E, Feng, Y, Rauskolb, C, Maitra, S, Fehon, R, and Irvine, KD (2006). Delineation of a Fat tumor suppressor pathway. Nat Genet. 38, 1142-1150.
    Pubmed CrossRef
  69. Poon, CL, Lin, JI, Zhang, X, and Harvey, KF (2011). The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway. Dev Cell. 21, 896-906.
    Pubmed CrossRef
  70. Boggiano, JC, Vanderzalm, PJ, and Fehon, RG (2011). Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway. Dev Cell. 21, 888-895.
    Pubmed KoreaMed CrossRef
  71. Chung, HL, Augustine, GJ, and Choi, KW (2016). Drosophila Schip1 Links Expanded and Tao-1 to Regulate Hippo Signaling. Dev Cell. 36, 511-524.
    Pubmed CrossRef
  72. Yu, J, Zheng, Y, Dong, J, Klusza, S, Deng, WM, and Pan, D (2010). Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell. 18, 288-299.
    Pubmed KoreaMed CrossRef
  73. Genevet, A, Wehr, MC, Brain, R, Thompson, BJ, and Tapon, N (2010). Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev Cell. 18, 300-308.
    Pubmed KoreaMed CrossRef
  74. Baumgartner, R, Poernbacher, I, Buser, N, Hafen, E, and Stocker, H (2010). The WW domain protein Kibra acts upstream of Hippo in Drosophila. Dev Cell. 18, 309-316.
    Pubmed CrossRef
  75. Su, T, Ludwig, MZ, Xu, J, and Fehon, RG (2017). Kibra and Merlin Activate the Hippo Pathway Spatially Distinct from and Independent of Expanded. Dev Cell. 40, 478-490 e473.
    Pubmed KoreaMed CrossRef
  76. Thompson, BJ, Pichaud, F, and Roper, K (2013). Sticking together the Crumbs - an unexpected function for an old friend. Nat Rev Mol Cell Biol. 14, 307-314.
    Pubmed CrossRef
  77. Chen, CL, Gajewski, KM, and Hamaratoglu, F (2010). The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila. Proc Natl Acad Sci U S A. 107, 15810-15815.
    Pubmed KoreaMed CrossRef
  78. Ling, C, Zheng, Y, and Yin, F (2010). The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc Natl Acad Sci U S A. 107, 10532-10537.
    Pubmed KoreaMed CrossRef
  79. Grzeschik, NA, Parsons, LM, Allott, ML, Harvey, KF, and Richardson, HE (2010). Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr Biol. 20, 573-581.
    Pubmed CrossRef
  80. Varelas, X, Samavarchi-Tehrani, P, and Narimatsu, M (2010). The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway. Dev Cell. 19, 831-844.
    Pubmed CrossRef
  81. Hirano, S, Kimoto, N, Shimoyama, Y, Hirohashi, S, and Takeichi, M (1992). Identification of a neural alpha-catenin as a key regulator of cadherin function and multicellular organization. Cell. 70, 293-301.
    Pubmed CrossRef
  82. Herrenknecht, K, Ozawa, M, Eckerskorn, C, Lottspeich, F, Lenter, M, and Kemler, R (1991). The uvomorulin-anchorage protein alpha catenin is a vinculin homologue. Proc Natl Acad Sci U S A. 88, 9156-9160.
    Pubmed KoreaMed CrossRef
  83. Silvis, MR, Kreger, BT, and Lien, WH (2011). alpha-catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator Yap1. Sci Signal. 4, ra33.
    CrossRef
  84. Wei, SY, Escudero, LM, and Yu, F (2005). Echinoid is a component of adherens junctions that cooperates with DE-Cadherin to mediate cell adhesion. Dev Cell. 8, 493-504.
    Pubmed CrossRef
  85. Yue, T, Tian, A, and Jiang, J (2012). The cell adhesion molecule echinoid functions as a tumor suppressor and upstream regulator of the Hippo signaling pathway. Dev Cell. 22, 255-267.
    Pubmed KoreaMed CrossRef
  86. Nishioka, N, Inoue, K, and Adachi, K (2009). The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell. 16, 398-410.
    Pubmed CrossRef
  87. Wang, W, Huang, J, and Wang, X (2012). PTPN14 is required for the density-dependent control of YAP1. Genes Dev. 26, 1959-1971.
    Pubmed KoreaMed CrossRef
  88. Liu, X, Yang, N, and Figel, SA (2013). PTPN14 interacts with and negatively regulates the oncogenic function of YAP. Oncogene. 32, 1266-1273.
    CrossRef
  89. Michaloglou, C, Lehmann, W, and Martin, T (2013). The tyrosine phosphatase TPN14 is a negative regulator of YAP activity. PLoS One. 8, e61916.
    CrossRef
  90. Moon, S, Kim, W, and Kim, S (2017). Phosphorylation by NLK inhibits YAP-14-3-3-interactions and induces its nuclear localization. EMBO Rep. 18, 61-71.
    CrossRef
  91. Dupont, S, Morsut, L, and Aragona, M (2011). Role of YAP/TAZ in mechanotransduction. Nature. 474, 179-183.
    Pubmed CrossRef
  92. Halder, G, Dupont, S, and Piccolo, S (2012). Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nat Rev Mol Cell Biol. 13, 591-600.
    Pubmed CrossRef
  93. Panciera, T, Azzolin, L, Cordenonsi, M, and Piccolo, S (2017). Mechanobiology of YAP and TAZ in physiology and disease. Nat Rev Mol Cell Biol. 12, 758-770.
    CrossRef
  94. Zhao, B, Li, L, Wang, L, Wang, CY, Yu, J, and Guan, KL (2012). Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev. 26, 54-68.
    Pubmed KoreaMed CrossRef
  95. Kim, NG, and Gumbiner, BM (2015). Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-I3K pathway. J Cell Biol. 210, 503-515.
    Pubmed KoreaMed CrossRef
  96. Elosegui-Artola, A, Andreu, I, and Beedle, AEM (2017). Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores. Cell. 171, 1397-1410.
    Pubmed CrossRef
  97. Mo, JS (2017). The role of extracellular biophysical cues in modulating the Hippo-YAP pathway. BMB Rep. 50, 71-78.
    KoreaMed CrossRef
  98. Wang, Z, Wu, Y, and Wang, H (2014). Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Proc Natl Acad Sci U S A. 111, E89-98.
    KoreaMed CrossRef
  99. Sorrentino, G, Ruggeri, N, and Specchia, V (2014). Metabolic control of YAP and TAZ by the mevalonate pathway. Nat Cell Biol. 16, 357-366.
    Pubmed CrossRef
  100. Mo, JS, Meng, Z, and Kim, YC (2015). Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat Cell Biol. 17, 500-510.
    Pubmed KoreaMed CrossRef
  101. Wang, W, Xiao, ZD, and Li, X (2015). AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat Cell Biol. 17, 490-499.
    Pubmed KoreaMed CrossRef
  102. Zhang, X, Qiao, Y, and Wu, Q (2017). The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis. Nat Commun. 8, 15280.
    Pubmed KoreaMed CrossRef
  103. Peng, C, Zhu, Y, and Zhang, W (2017). Regulation of the Hippo-YAP Pathway by Glucose Sensor O-GlcNAcylation. Mol Cell. 68, 591-604 e595.
    Pubmed CrossRef
  104. Ma, B, Chen, Y, and Chen, L (2015). Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase. Nat Cell Biol. 17, 95-103.
    CrossRef
  105. Ma, X, Zhang, H, Xue, X, and Shah, YM (2017). Hypoxia-inducible factor 2alpha (HIF-2alpha) promotes colon cancer growth by potentiating Yes-associated protein 1 (YAP1) activity. J Biol Chem. 292, 17046-17056.
    Pubmed KoreaMed CrossRef
  106. Xiang, L, Gilkes, DM, and Hu, H (2014). Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype. Oncotarget. 5, 12509-12527.
    CrossRef
  107. Ma, B, Cheng, H, and Gao, R (2016). Zyxin-Siah2-Lats2 axis mediates cooperation between Hippo and TGF-beta signalling pathways. Nat Commun. 7, 11123.
    CrossRef
  108. Hong, AW, Meng, Z, and Yuan, HX (2017). Osmotic stress-induced phosphorylation by NLK at Ser128 activates YAP. EMBO Rep. 18, 72-86.
    CrossRef
  109. Lin, KC, Moroishi, T, and Meng, Z (2017). Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation. Nat Cell Biol. 19, 996-1002.
    Pubmed KoreaMed CrossRef
  110. Taylor, LK, Wang, HC, and Erikson, RL (1996). Newly identified stress-responsive protein kinases, Krs-1 and Krs-2. Proc Natl Acad Sci U S A. 93, 10099-10104.
    Pubmed KoreaMed CrossRef
  111. Lehtinen, MK, Yuan, Z, and Boag, PR (2006). A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell. 125, 987-1001.
    Pubmed CrossRef
  112. Shao, D, Zhai, P, and Del Re, DP (2014). A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response. Nat Commun. 5, 3315.
    Pubmed KoreaMed CrossRef
  113. Nusse, R, and Clevers, H (2017). Wnt/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell. 169, 985-999.
    Pubmed CrossRef
  114. Kim, W, Kim, M, and Jho, EH (2013). Wnt/beta-catenin signalling: from plasma membrane to nucleus. Biochem J. 450, 9-21.
    Pubmed CrossRef
  115. Varelas, X, Miller, BW, and Sopko, R (2010). The Hippo pathway regulates Wnt/beta-catenin signaling. Dev Cell. 18, 579-591.
    Pubmed CrossRef
  116. Imajo, M, Miyatake, K, Iimura, A, Miyamoto, A, and Nishida, E (2012). A molecular mechanism that links Hippo signalling to the inhibition of Wnt/beta-catenin signalling. EMBO J. 31, 1109-1122.
    Pubmed KoreaMed CrossRef
  117. Barry, ER, Morikawa, T, and Butler, BL (2013). Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature. 493, 106-110.
    KoreaMed CrossRef
  118. Tsutsumi, R, Masoudi, M, and Takahashi, A (2013). YAP and TAZ, Hippo signaling targets, act as a rheostat for nuclear SHP2 function. Dev Cell. 26, 658-665.
    Pubmed CrossRef
  119. Heallen, T, Zhang, M, and Wang, J (2011). Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science. 332, 458-461.
    Pubmed KoreaMed CrossRef
  120. Kim, W, Khan, SK, and Gvozdenovic-Jeremic, J (2017). Hippo signaling interactions with Wnt/beta-catenin and Notch signaling repress liver tumorigenesis. J Clin Invest. 127, 137-152.
    CrossRef
  121. Fitamant, J, Kottakis, F, and Benhamouche, S (2015). YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression. Cell Rep. 10, 1692-1707.
    CrossRef
  122. Azzolin, L, Zanconato, F, and Bresolin, S (2012). Role of TAZ as mediator of Wnt signaling. Cell. 151, 1443-1456.
    Pubmed CrossRef
  123. Azzolin, L, Panciera, T, and Soligo, S (2014). YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell. 158, 157-170.
    Pubmed CrossRef
  124. Cai, J, Maitra, A, Anders, RA, Taketo, MM, and Pan, D (2015). beta-Catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis. Genes Dev. 29, 1493-1506.
    Pubmed KoreaMed CrossRef
  125. Yu, FX, Zhao, B, and Panupinthu, N (2012). Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell. 150, 780-791.
    Pubmed KoreaMed CrossRef
  126. Miller, E, Yang, J, and DeRan, M (2012). Identification of serum-derived sphingosine-1-phosphate as a small molecule regulator of YAP. Chem Biol. 19, 955-962.
    CrossRef
  127. Park, HW, Kim, YC, and Yu, B (2015). Alternative Wnt Signaling Activates YAP/TAZ. Cell. 162, 780-794.
    Pubmed KoreaMed CrossRef
  128. Struhl, G, Fitzgerald, K, and Greenwald, I (1993). Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo. Cell. 74, 331-345.
    Pubmed CrossRef
  129. Schroeter, EH, Kisslinger, JA, and Kopan, R (1998). Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature. 393, 382-386.
    Pubmed CrossRef
  130. Bray, SJ (2016). Notch signalling in context. Nat Rev Mol Cell Biol. 17, 722-735.
    Pubmed CrossRef
  131. Meignin, C, Alvarez-Garcia, I, Davis, I, and Palacios, IM (2007). The salvador-warts-hippo pathway is required for epithelial proliferation and axis specification in Drosophila. Curr Biol. 17, 1871-1878.
    Pubmed KoreaMed CrossRef
  132. Polesello, C, and Tapon, N (2007). Salvador-warts-hippo signaling promotes Drosophila posterior follicle cell maturation downstream of notch. Curr Biol. 17, 1864-1870.
    Pubmed CrossRef
  133. Camargo, FD, Gokhale, S, and Johnnidis, JB (2007). YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol. 17, 2054-2060.
    Pubmed CrossRef
  134. Zhou, D, Zhang, Y, and Wu, H (2011). Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance. Proc Natl Acad Sci U S A. 108, E1312-1320.
    Pubmed KoreaMed CrossRef
  135. Yimlamai, D, Christodoulou, C, and Galli, GG (2014). Hippo pathway activity influences liver cell fate. Cell. 157, 1324-1338.
    Pubmed KoreaMed CrossRef
  136. Manderfield, LJ, Aghajanian, H, and Engleka, KA (2015). Hippo signaling is required for Notch-dependent smooth muscle differentiation of neural crest. Development. 142, 2962-2971.
    Pubmed KoreaMed CrossRef
  137. Rayon, T, Menchero, S, and Nieto, A (2014). Notch and hippo converge on Cdx2 to specify the trophectoderm lineage in the mouse blastocyst. Dev Cell. 30, 410-422.
    Pubmed KoreaMed CrossRef
  138. Tschaharganeh, DF, Chen, X, and Latzko, P (2013). Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma. Gastroenterology. 144, 1530-1542 e1512.
    Pubmed KoreaMed CrossRef
  139. Massague, J (2012). TGFbeta signalling in context. Nat Rev Mol Cell Biol. 13, 616-630.
    CrossRef
  140. Luo, K (2017). Signaling Cross Talk between TGF-beta/Smad and Other Signaling Pathways. Cold Spring Harb Perspect Biol. 9, a022137.
    CrossRef
  141. Ayyaz, A, Attisano, L, and Wrana, JL (2017). Recent advances in understanding contextual TGFbeta signaling. F1000 Res. 6, 749.
    CrossRef
  142. Attisano, L, and Wrana, JL (2013). Signal integration in TGF-beta, WNT, and Hippo pathways. F1000 Prime Rep. 5, 17.
    CrossRef
  143. Varelas, X, Sakuma, R, and Samavarchi-Tehrani, P (2008). TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol. 10, 837-848.
    Pubmed CrossRef
  144. Nallet-Staub, F, Yin, X, and Gilbert, C (2015). Cell density sensing alters TGF-beta signaling in a cell-type-specific manner, independent from Hippo pathway activation. Dev Cell. 32, 640-651.
    Pubmed KoreaMed CrossRef
  145. Mahoney, JE, Mori, M, Szymaniak, AD, Varelas, X, and Cardoso, WV (2014). The hippo pathway effector Yap controls patterning and differentiation of airway epithelial progenitors. Dev Cell. 30, 137-150.
    Pubmed CrossRef
  146. Zhao, R, Fallon, TR, and Saladi, SV (2014). Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells. Dev Cell. 30, 151-165.
    Pubmed KoreaMed CrossRef
  147. Lee, DH, Park, JO, and Kim, TS (2016). LATS-YAP/TAZ controls lineage specification by regulating TGFbeta signaling and Hnf4alpha expression during liver development. Nat Commun. 7, 11961.
    CrossRef
  148. Lai, D, and Yang, X (2013). BMP4 is a novel transcriptional target and mediator of mammary cell migration downstream of the Hippo pathway component TAZ. Cell Signal. 25, 1720-1728.
    Pubmed CrossRef
  149. Nishio, M, Sugimachi, K, and Goto, H (2016). Dysregulated YAP1/TAZ and TGF-beta signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice. Proc Natl Acad Sci U S A. 113, E71-80.
    CrossRef
  150. Pefani, DE, Pankova, D, and Abraham, AG (2016). TGF-beta Targets the Hippo Pathway Scaffold RASSF1A to Facilitate YAP/SMAD2 Nuclear Translocation. Mol Cell. 63, 156-166.
    Pubmed CrossRef
  151. Stroschein, SL, Wang, W, Zhou, S, Zhou, Q, and Luo, K (1999). Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science. 286, 771-774.
    Pubmed CrossRef
  152. Zhu, Q, Le Scolan, E, Jahchan, N, Ji, X, Xu, A, and Luo, K (2016). SnoN Antagonizes the Hippo Kinase Complex to Promote TAZ Signaling during Breast Carcinogenesis. Dev Cell. 37, 399-412.
    Pubmed KoreaMed CrossRef


This Article


Cited By Articles
  • CrossRef (0)

Funding Information

Services
Social Network Service

e-submission

Archives