YAP Signaling Research Articles

A miR-130a-YAP positive feedback loop promotes organ size and tumorigenesis.

Organ size determination is one of the most intriguing unsolved mysteries in biology. Aberrant activation of the major effector and transcription co-activator YAP in the Hippo pathway causes drastic organ enlargement in development and underlies tumorigenesis in many human cancers. However, how robust YAP activation is achieved during organ size control remains elusive. Here we report that the YAP signaling is sustained through a novel microRNA-dependent positive feedback loop. miR-130a, which is directly induced by YAP, could effectively repress VGLL4, an inhibitor of YAP activity, thereby amplifying the YAP signals. Inhibition of miR-130a reversed liver size enlargement induced by Hippo pathway inactivation and blocked YAP-induced tumorigenesis. Furthermore, the Drosophila Hippo pathway target bantam functionally mimics miR-130a by repressing the VGLL4 homolog SdBP/Tgi. These findings reveal an evolutionarily conserved positive feedback mechanism underlying robustness of the Hippo pathway in size control and tumorigenesis.

Phosphorylation of the Hippo Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness

The mechanistic target of rapamycin (mTOR) and Hippo signaling pathways are two major signaling cascades that coordinately regulate cell growth and proliferation. Dysregulation of these pathways plays a critical role in gliomagenesis. Recent reports have provided evidence of cross-talk between the mTOR and Hippo pathways; however, a complete description of the signaling relationships between these pathways remains to be elucidated. Utilizing a gene-trapping strategy in a mouse glioma model, we report the identification of AMOTL2 as a candidate substrate for mTORC2. AMOTL2 is phosphorylated at serine 760 by mTORC2. Mutation of AMOTL2 mimicking constitutive Ser(760) phosphorylation blocks its ability to bind and repress YAP leading to increased relative expression of known YAP gene targets. Moreover, overexpression of AMOTL2 or a nonphosphorylatable AMOTL2-S760A mutant inhibited YAP-induced transcription, foci formation, growth, and metastatic properties, whereas overexpression of a phosphomimetic AMOTL2-S760E mutant negated these repressive effects of AMOTL2 in glioblastoma (GBM) cells in vitro. Similar effects on xenograft growth were observed in GBM cells expressing these AMOTL2 Ser(760) mutants. YAP was also shown to be required for Rictor-mediated GBM growth and survival. Finally, an analysis of mTORC2/AMOTL2/YAP activities in primary GBM samples supported the clinical relevance of this signaling cascade, and we propose that pharmacological agents cotargeting these regulatory circuits may hold therapeutic potential.

Abstract 1956: A subset of prostate cancer cells with loss of MST1 expression confers resistance to castration through YAP1-AR interactions

Abstract MST1 is a core kinase component of the Hippo tumor suppressor pathway. YAP1 is a transcriptional cofactor and a prominent nuclear effector of the Hippo signaling. YAP1 activation is linked to cancer promotion with poor prognosis. However, the role of MST1-YAP axis in prostate cancer (PC) progression remains unknown. Here we isolated MST1 high and MST1 low/- expressing cell subsets from a well-characterized LNCaP PC cell model by employing novel method that utilizes an epigenetically regulated-MST1 promoter-driven GFP reporter combined with FACS. We performed molecular and functional characterizations of these cells utilizing a wide variety of experimental approaches. We demonstrated that unlike MST1 high, MST1 low/- cells shared the features of cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) phenotype, showed superior osteogenic abilities, and were resistant to androgen depletion and enzalutamide (ENZ), a potent inhibitor of androgen receptor (AR). Consistently, silencing of MST1 expression by siRNA recapitulated the above molecular and function behaviors of MST1 low/- cells. In addition, MST1 low/- cells showed superior invasive growth abilities in vitro and tumor-forming abilities with metastatic potentials in mice compared with those of MST1 high cells. Moreover, relative YAP1 expression and its nuclear localization were much higher in MST1 low/- cells than MST1 high cells. Likewise, YAP1 protein levels and its nuclear abundance were increased in PC clinical samples compared to non-cancerous counters. We further showed that YAP1 interacted with AR in an androgen-dependent manner in LNCaP cells, whereas the interactions between the two proteins were androgen-independent (AI) in C4-2 CRPC cells. Furthermore we found that unlike LNCaP, YAP1-AR interactions were resistant to ENZ exposure in C4-2 cells. Consistently, silencing of MST1 in LNCaP cells augmented AI interactions between YAP1 and AR proteins. Finally, the disruption of YAP1 signaling by RNAi and Verteporfin (VP) attenuated C4-2 cell growth and promoted apoptosis, accompanied with the attenuation of AR-dependent gene expression. In conclusion, our findings suggest that the Hippo-YAP1-AR signaling axis is one of the key mechanisms for metastatic PC progression and may represent as a promising therapeutic target for patients with the lethal disease. Note: This abstract was not presented at the meeting. Citation Format: Bekir Cinar, Gamze Kuser Abali, Michael Lewis, Colm Morrissey, Isla Garraway. A subset of prostate cancer cells with loss of MST1 expression confers resistance to castration through YAP1-AR interactions. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1956. doi:10.1158/1538-7445.AM2015-1956

β-Catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis.

Mutations in Adenomatous polyposis coli (APC) underlie familial adenomatous polyposis (FAP), an inherited cancer syndrome characterized by the widespread development of colorectal polyps. APC is best known as a scaffold protein in the β-catenin destruction complex, whose activity is antagonized by canonical Wnt signaling. Whether other effector pathways mediate APC's tumor suppressor function is less clear. Here we report that activation of YAP, the downstream effector of the Hippo signaling pathway, is a general hallmark of tubular adenomas from FAP patients. We show that APC functions as a scaffold protein that facilitates the Hippo kinase cascade by interacting with Sav1 and Lats1. Consistent with the molecular link between APC and the Hippo signaling pathway, genetic analysis reveals that YAP is absolutely required for the development of APC-deficient adenomas. These findings establish Hippo-YAP signaling as a critical effector pathway downstream from APC, independent from its involvement in the β-catenin destruction complex.

Combining BET and HDAC inhibitors synergistically induces apoptosis of melanoma and suppresses AKT and YAP signaling.

Histone acetylation marks have an important role in controlling gene expression and are removed by histone deacetylases (HDACs). These marks are read by bromodomain and extra-terminal (BET) proteins and novel inhibitiors of these proteins are currently in clinical development. Inhibitors of HDAC and BET proteins have individually been shown to cause apoptosis and reduce growth of melanoma cells. Here we show that combining the HDAC inhibitor LBH589 and BET inhibitor I-BET151 synergistically induce apoptosis of melanoma cells but not of melanocytes. Induction of apoptosis proceeded through the mitochondrial pathway, was caspase dependent and involved upregulation of the BH3 pro-apoptotic protein BIM. Analysis of signal pathways in melanoma cell lines resistant to BRAF inhibitors revealed that treatment with the combination strongly downregulated anti-apoptotic proteins and proteins in the AKT and Hippo/YAP signaling pathways. Xenograft studies showed that the combination of inhibitors was more effective than single drug treatment and confirmed upregulation of BIM and downregulation of XIAP as seen in vitro. These results support the combination of these two classes of epigenetic regulators in treatment of melanoma including those resistant to BRAF inhibitors.

Combining BET and HDAC inhibitors to potentiate their effectiveness against melanoma and to suppress AKT and YAP signaling.

e13557 Background: Increasing evidence suggests that epigenetic changes underlie many of the oncogenic processes in melanoma. In previous studies we have shown that epigenetic regulation of gene ex...

Inactivation of a Gα(s)-PKA tumour suppressor pathway in skin stem cells initiates basal-cell carcinogenesis.

Genomic alterations in GNAS, the gene coding for the Gαs heterotrimeric G-protein, are associated with a large number human of diseases. Here, we explored the role of Gαs on stem cell fate decisions by using the mouse epidermis as a model system. Conditional epidermal deletion of Gnas or repression of PKA signaling caused a remarkable expansion of the stem cell compartment, resulting in rapid basal cell carcinoma formation. In contrast, inducible expression of active Gαs in the epidermis caused hair follicle stem cell exhaustion and hair loss. Mechanistically, we found that Gαs-PKA disruption promotes the cell autonomous Sonic Hedgehog pathway stimulation and Hippo signaling inhibition, resulting in the non-canonical activation of GLI and YAP1. Our study highlights an important tumor suppressive function of Gαs-PKA, limiting the proliferation of epithelial stem cells and maintaining proper hair follicle homeostasis. These findings can have broad implications in multiple pathophysiological conditions, including cancer.

MP19-05 THE HIPPO/MST PATHWAY IS A CRUCIAL PART OF THE BLADDER SMC RESPONSE TO INJURY

You have accessJournal of UrologyStem Cell Research1 Apr 2015MP19-05 THE HIPPO/MST PATHWAY IS A CRUCIAL PART OF THE BLADDER SMC RESPONSE TO INJURY KJ Aitken, Martin Sidler, Alaleh Samiei, Paul Delgado-Olguin, and Darius Bagli KJ AitkenKJ Aitken More articles by this author , Martin SidlerMartin Sidler More articles by this author , Alaleh SamieiAlaleh Samiei More articles by this author , Paul Delgado-OlguinPaul Delgado-Olguin More articles by this author , and Darius BagliDarius Bagli More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.997AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In many organ systems, the Hippo/MST pathway controls growth and differentiation responses to mechanical stimuli. MST, the mammalian homologue of Hippo, negatively regulates growth through the phosphorylation of YAP and TAZ. This phosphorylation prevents nuclear localization that is required for function of YAP/TAZ. In muscle cells, the association of YAP or TAZ with specific TEADs can promote either differentiation or growth. While this pathway has been shown to be critical for developmental of the bladder, little is known concerning the regulation of MST and its downstream partners in bladder smooth muscle models of mechanical stress including in vitro strain and the mechanical stimulus of in vivo obstruction. METHODS Rat Sprague-Dawley bladder smooth muscle cells (BSMC) isolated from neonatal (days 1–3) pups by collagenase treatment were cultured in EMEM with low serum. BSMC were exposed to mechanical strain (5% elongation) or remained unstrained. Partial bladder outlet obstruction (PBO) of Sprague-Dawley female rats (n=8) was induced by suturing with a silk suture around a 0.9 mm steel rod, then removing the rod. Controls included sham-operated rats (n=6). Bladders were obstructed for 6 weeks and harvested for RNA by flash freezing and for sectioning by embedding in OCT. QPCR was performed key MST pathway members (MST, YAP, TAZ, TEADs 1–4) and YAP downstream targets. YAP/TAZ nuclear localization, which indicates activation, was studied by immunofluorescence. RESULTS During mechanical strain, expression of YAP mRNA was maintained, while TAZ mRNA expression was significantly decreased (p<0.05). A 27-fold reduction (p<0.05) in MST1 mRNA expression during mechanical strain was consistent with an observed increase YAP protein nuclear localization (p<0.03). TAZ was also downregulated during PBO (p<0.01). YAP localization was correlated with increased hypertrophy, but YAP mRNA did not change. MST1 mRNA expression showed a non-significant downregulation during PBO. Transcriptional targets of YAP/TAZ were upregulated during mechanical strain and obstruction (p<0.03). TEADs mRNA did not change significantly. CONCLUSIONS YAP activation in the Hippo/MST pathway is associated with growth during mechanical strain of the bladder. Further work to understand the mechanisms of YAP signalling, TAZ downregulation and specific interactions with transcription binding partners during strain and obstruction will provide insight into mechanisms of both hypertrophy and normal growth in the bladder. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e217 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information KJ Aitken More articles by this author Martin Sidler More articles by this author Alaleh Samiei More articles by this author Paul Delgado-Olguin More articles by this author Darius Bagli More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver.

Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk between the PI3K and Yap pathways along liver carcinogenesis, we generated a mouse model characterized by combined overexpression of activated mutant forms of PIK3CA (PIK3CAH1047R) and Yap (YapS127A) in the mouse liver using hydrodynamic transfection (PIK3CA/Yap). In addition, suppression of PI3K and Yap pathways was conducted in human HCC and cholangiocarcinoma (CCA) cell lines. We found that concomitant activation of PI3K and Yap pathways triggered rapid liver tumor development in mice. Histologically, tumors were pure HCC, CCA, or mixed HCC/CCA. At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways. Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines. In conclusion, our study demonstrates the oncogenic cooperation between PI3K and Yap pathways along liver carcinogenesis. The PIK3CA/Yap mouse represents an important preclinical liver tumor model for the development of novel therapeutics against this malignancy.

Neuregulin 1-activated ERBB4 as a "dedicated" receptor for the Hippo-YAP pathway.

The Hippo tumor-suppressor pathway is regulated by several multicomponent complexes of cell polarity and cell-to-cell junctions. Hippo kinases inhibit the transcription coactivator YAP. In contrast to the orthologous pathway in Drosophila, in which the single transmembrane receptor Fat and its ligand Dachsous are "dedicated" to trigger the pathway, the mammalian Hippo-YAP pathway was without such a dedicated receptor. In this issue of Science Signaling, a study by Haskins et al. has brought an end to this scenario of an "orphaned" pathway by identifying neuregulin 1 and its cognate receptor ERBB4 [epidermal growth factor receptor (EGFR) family member v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4] as a major receptor complex that activates YAP activity. Moreover, the identification of ERBB4 as a dominant receptor of YAP signaling brings into focus the signaling interface between the EGFR signaling axis and the Hippo-YAP network, with numerous implications for basic and applied cancer research.

Energy Stress Regulates the Hippo–YAP Pathway

Abstract Activation of AMPK in response to energy stress inhibits YAP signaling via regulation of AMOTL1.

Nf2–Yap signaling controls the expansion of DRG progenitors and glia during DRG development

Molecular mechanisms governing the maintenance and proliferation of dorsal root ganglia (DRG) progenitors are largely unknown. Here we reveal that the Hippo pathway regulates the expansion of DRG progenitors and glia during mammalian DRG development. The key effectors of this pathway, transcriptional coactivators Yap and Taz, are expressed in DRG progenitors and glia during DRG development but are at least partially inhibited from activating transcription. Aberrant YAP activation leads to overexpansion of DRG progenitor and glial populations. We further show that the Neurofibromatosis 2 (Nf2) tumor suppressor inhibits Yap during DRG development. Loss of Nf2 leads to similar phenotypes as does YAP hyperactivation, and deleting Yap suppresses these phenotypes. Our study demonstrates that Nf2–Yap signaling plays important roles in controlling the expansion of DRG progenitors and glia during DRG development.

Expression Profiles and Clinicopathologic Features in Early Resected Non-small-cell Lung Cancer

Expression Profiles and Clinicopathologic Features in Early Resected Non-small-cell Lung Cancer

Silencing of Yap Gene Inhibits Metastasis in a Severe Combined Immune Deficiency Mice Orthotopic Implantation Gastric Cancer Model

YAP signaling has been proved to be involved in cell growth, invasion and metastasis in multiple malignancies. But little has been reported about the effects of YAP transduction on gastric cancer metastases. The present study was aimed to explore the effects of shRNA-mediated targeting of YAP gene on human gastric cancer metastases in severe combined immune deficiency (SCID) mice. Human gastric carcinoma cell line SGC7901 was implanted into the stomach of SCID mice, which were randomly divided into 3 groups (n=10). Via intraperitoneal injection, mice received YAP-shRNA, negative control, or normal saline respectively. The results of TUNEL and FQ-PCR showed an obvious induction of apoptosis in the YAP-shRNA group. Intratumoral vascular density and lymphatic density were suppressed in the YAP-shRNA group. In conclusion, silencing of YAP gene effectively induces the cell apoptosis and inhibits microvascular angiogenesis and lymphagiogenesis of gastric cancer cells in vivo, suggesting that YAP may serve as a promising therapeutic target for treatment of cancer.

CD44 acts through RhoA to regulate YAP signaling

The Hippo pathway plays an important role in both physical and pathogenesis processes. As crucial downstream effectors of Hippo pathway, YAP is inhibited by Lats1/2 through phosphorylation. However, upstream signals that regulate the Hippo pathway have been still poorly understood. Here, we found that knockdown of CD44 reduced YAP expression and nuclear localization, but nearly had no effect on its upstream effectors, Mst1 and Lats1. Downregulated CD44 expression also significantly decreased the expression of YAP downstream effectors CTGF, Cyr61 and EDN1 at mRNA level. Our next study showed that knockdown of CD44 inhibited RhoA expression, which was consistent with RhoA knockdown mediated YAP downregulation. Furthermore, we demonstrated that over expression of the constitutively active RhoA (RhoA-V14) could block the YAP expression decrease mediated by CD44 knockdown. Moreover, downregulation of CD44 significantly promoted cell apoptosis and inhibited cell proliferation, cell cycle progression and migration, which were consistent with the effects of RNAi-mediated YAP knockdown in both A549 and HepG2 cells. Overall, data are presented showing that CD44 could act through RhoA signaling to regulate YAP expression and this study also provide new insights into the regulatory mechanisms of the Hippo–YAP pathway.

KRAS and YAP1 Converge to Regulate EMT and Tumor Survival

Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival upon KRAS suppression. In particular, the transcriptional coactivator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling.

Activation of β-Catenin and Yap1 in Human Hepatoblastoma and Induction of Hepatocarcinogenesis in Mice

Aberrant activation of β-catenin and Yes-associated protein 1 (Yap1) signaling pathways have been associated with the development of multiple tumor types. Yap functions as a transcriptional coactivator by interacting with TEA domain DNA binding proteins. We investigated the interactions among these pathways during hepatic tumorigenesis. We used immunohistochemical analysis to determine expression of β-catenin and Yap1 in liver cancer specimens collected from patients in Europe and the United States, consisting of 104 hepatocellular carcinoma, 62 intrahepatic cholangiocarcinoma, and 94 hepatoblastoma samples. We assessed β-catenin and Yap1 signaling and interactions in hepatoblastoma cell lines ((HuH6, HepG2, HepT1, HC-AFW1, HepG2, and HC-AFW1); proteins were knocked down with small interfering RNAs, and effects on proliferation and cell death were measured. Sleeping beauty-mediated hydrodynamic transfection was used to overexpress constitutively active forms of β-catenin (ΔN90/β-catenin) and Yap1 (YapS127A) in livers of mice; tissues were collected, and histological and immunohistochemical analyses were performed. We observed nuclear localization of β-catenin and Yap1 in 79% of hepatoblastoma samples but not in most hepatocellular carcinoma or intrahepatic cholangiocarcinoma samples. Yap1 and β-catenin coprecipitated in hepatoblastoma but not hepatocellular carcinoma cells. Small interfering RNA-mediated knockdown of Yap1 or β-catenin in hepatoblastoma cells reduced proliferation in an additive manner. Knockdown of Yap1 reduced its ability to coactivate transcription with β-catenin; β-catenin inhibitors inactivated Yap1. Overexpression of constitutively active forms of Yap1 and β-catenin in mouse liver led to rapid tumorigenesis, with 100% mortality by 11 weeks. Tumor cells expressed both proteins, and human hepatoblastoma cells expressed common targets of their 2 signaling pathways. Yap1 binding of TEA domain factors was required for tumorigenesis in mice. β-catenin and the transcriptional regulator Yap1 interact physically and are activated in most human hepatoblastoma tissues; overexpression of activated forms of these proteins in livers of mice leads to rapid tumor development. Further analysis of these mice will allow further studies of these pathways in hepatoblastoma pathogenesis and could lead to the identification of new therapeutic targets.

Interrelationship between acinar zymogen activation, cell injury and inflammation in experimental acute pancreatitis

s / Pancreatology 13 (2013) e1–e94 e8 tamoxifen-induced Ela-Cre-ERT2;Yapflox/flox mice resulted in severe (“necrotizing”) pancreatitis, including the onset of mortality, compared to littermates with retained pancreatic Yap expression. Transcriptional profiling confirmed the failure to induce multiple anti-apoptotic molecules, including survivin, in the absence of Yap protein, which was accompanied by an increase in acinar cell apoptosis. However, neither exocrine regeneration itself, nor the upregulation of canonical signaling pathways implicated in regeneration (Notch and Hedgehog), was significantly abrogated in the absence of Yap. Thus, an intact Hippo pathway is essential for pancreatic morphogenesis during embryonic development. While in the mature pancreas, absence of Yap profoundly exacerbates exocrine pancreatitis. Systemic therapeutics directed at negating YAP function in cancer cells need to be cognizant of the requirement for sustained YAP signaling in embryonic and mature tissues.

Correction: The role of LPA and YAP signaling in long-term migration of human ovarian cancer cells

Correction: The role of LPA and YAP signaling in long-term migration of human ovarian cancer cells

The role of LPA and YAP signaling in long-term migration of human ovarian cancer cells.

BackgroundThe Hippo-YAP signaling pathway is altered and implicated as oncogenic in many human cancers. However, extracellular signals that regulate the mammalian Hippo pathway have remained elusive until very recently when it was shown that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) ligands including lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P). LPA inhibits Lats kinase activity in HEK293 cells, but the potential involvement of a protein phosphatase was not investigated. The extracellular regulators of YAP dephosphorylation (dpYAP) and nuclear translocation in epithelial ovarian cancer (EOC) are essentially unknown.ResultsWe showed here that LPA dose- and time-dependently induced dpYAP in human EOC cell lines OVCA433, OVCAR5, CAOV3, and Monty-1, accompanied by increased YAP nuclear translocation. YAP was involved in LPA-induced migration and invasion of EOC cells and LPA3 was a major LPA receptor mediating the migratory effect. We demonstrated that G13, but not or to a lesser extent G12, Gi or Gq, was necessary for LPA-induced dpYAP and its nuclear translocation and that RhoA-ROCK, but not RhoB, RhoC, Rac1, cdc42, PI3K, ERK, or AKT, were required for the LPA-dpYAP effect. In contrast to results in HEK293 cells, LPA did not inhibit Mst and Lats kinase in OVCA433 EOC cells. Instead, protein phosphatase 1A (PP1A) acted down-stream of RhoA in LPA-induction of dpYAP. In addition, we identified that amphiregulin (AREG), a down-stream target of YAP which activated EGF receptors (EGFR), mediated an LPA-stimulated and EGFR-dependent long-term (16 hr) cell migration. This process was transcription- and translation-dependent and was distinct from a transcription- and YAP-independent short-term (4 hr) cell migration. EOC tissues had reduced pYAP levels compared to normal and benign ovarian tissues, implying the involvement of dpYAP in EOC pathogenesis, as well as its potential marker and/or target values.ConclusionsA novel LPA-LPA3-G13-RhoA-ROCK-PP1A-dpYAP-AREG-EGFR signaling pathway was linked to LPA-induced migration of EOC cells. Reduced pYAP levels were demonstrated in human EOC tumors as compared to both normal ovarian tissues and benign gynecologic masses. Our findings support that YAP is a potential marker and target for developing novel therapeutic strategies against EOC.