The Hippo component YAP localizes in the nucleus of human papilloma virus positive oropharyngeal squamous cell carcinoma
- Faisal Alzahrani1,
- Leanne Clattenburg2,
- Shanmugam Muruganandan2,
- Martin Bullock3,
- Kaitlyn MacIsaac2,
- Michael Wigerius2,
- Blair A. Williams1,
- M. Elise R. Graham1,
- Matthew H. Rigby1,
- Jonathan R. B. Trites1,
- S. Mark Taylor1,
- Christopher J. Sinal2,
- James P. Fawcett1, 2Email author and
- Robert D. Hart1Email author
© The Author(s). 2017
Received: 7 September 2016
Accepted: 2 February 2017
Published: 22 February 2017
HPV infection causes cervical cancer, mediated in part by the degradation of Scribble via the HPV E6 oncoprotein. Recently, Scribble has been shown to be an important regulator of the Hippo signaling cascade. Deregulation of the Hippo pathway induces an abnormal cellular transformation, epithelial to mesenchymal transition, which promotes oncogenic progression. Given the recent rise in oropharyngeal HPV squamous cell carcinoma we sought to determine if Hippo signaling components are implicated in oropharyngeal squamous cell carcinoma.
Molecular and cellular techniques including immunoprecipiations, Western blotting and immunocytochemistry were used to identify the key Hippo pathway effector Yes-Associated Protein (YAP)1. Oropharyngeal tissue was collected from CO2 laser resections, and probed with YAP1 antibody in tumor and pre-malignant regions of HPV positive OPSCC tissue.
This study reveals that the Scribble binding protein Nitric Oxide Synthase 1 Adaptor Protein (NOS1AP) forms a complex with YAP. Further, the NOS1APa and NOS1APc isoforms show differential association with activated and non-activated YAP, and impact cellular proliferation. Consistent with deregulated Hippo signaling in OPSCC HPV tumors, we see a delocalization of Scribble and increased nuclear accumulation of YAP1 in an HPV-positive OPSCC.
Our preliminary data indicates that NOS1AP isoforms differentially associate with YAP1, which, together with our previous findings, predicts that loss of YAP1 enhances cellular transformation. Moreover, YAP1 is highly accumulated in the nucleus of HPV-positive OPSCC, implying that Hippo signaling and possibly NOS1AP expression are de-regulated in OPSCC. Further studies will help determine if NOS1AP isoforms, Scribble and Hippo components will be useful biomarkers in OPSCC tumor biology.
KeywordsHPV p16 Oropharyngeal squamous cell carcinoma Hippo YAP Scribble NOS1AP
Oropharyngeal squamous cell carcinoma (OPSCC) has traditionally been a disease associated with long-term use of tobacco and alcohol. In recent decades there has been a shift in the demographics of the OPSCC patient: the majority are now younger, otherwise healthy, non-drinkers and non-smokers. It is widely accepted that this shift is secondary to infection with Human Papilloma Virus (HPV). HPV-16 is commonly associated with a high risk of carcinogenesis, and is found in up to 90% of HPV positive OPSCCs [1–3]. The molecular mechanism of HPV-induced carcinogenesis has been well studied in cervical cancer and there is a growing body of literature concerning its effects in the oropharynx.
HPV is a small virus that infects squamous epithelium. It gives rise to two clusters of proteins: early (E1-7) and late (L1-2). The early genes E5, E6, and E7 all give rise to oncoproteins with the remaining genes coding for regulatory and structural proteins . The oncoprotein E6 causes ubiquitin mediated degradation of the tumor suppressor P53, leading to a reduced rate of apoptosis . The oncoproteins from low-risk HPV strains (e.g. HPV-6) are unable to target tumor suppressor proteins as efficiently as high risk strains such as HPV-16 .
In addition to E6 degrading p53, recent studies have shown a direct interaction between the HPV E6 protein and the tumor suppressor protein Scribble, leading to the degradation of Scribble [5, 6]. This interaction initiates epithelial to mesenchymal transition (EMT) transition, an early event in cellular transformation and oncogenesis .
Epithelial polarity is a fundamental process in cellular growth and contact inhibition. Disruption of cellular polarity is a major contributor to carcinogenesis. Scribble is a tumour suppressor protein that localizes to the basolateral margins of polarized epithelial cells and plays a major role in establishing cellular polarity . Scribble has also been linked to the intracellular transduction pathway known as Hippo [9, 10]. Activation of the well established Hippo cascade leads to the phosphorylation and inactivation of Yes Associated Protein (YAP)1, (hereafter referred to as YAP) and its retention in the cytoplasm, whereas YAP dephosphorylation and activation locates it in the nucleus where it drives cellular proliferation . Deregulation of the Hippo pathway occurs in a broad range of human carcinomas, including lung, colorectal, breast, ovarian, pancreatic, gastric and liver cancers [11–19]. YAP deregulation has been implicated in other head and neck malignancies [20, 21], and its expression has been associated with poor patient survival in esophageal cancers . Increased YAP levels and nuclear sequestration were associated with high-grade oral squamous cell carcinoma (OSCC) , but it is currently unknown if Hippo pathway deregulation plays a role in OPSCC.
The improved survival and increased susceptibility of HPV positive OPSCC to treatment has led to optimism. Improved understanding of the mechanisms of HPV modulated oncogenesis by different molecular carcinogenic pathways can help in better understanding of tumorgenesis and may lead to more effective targeted therapy in the future. Given the recent rise in oropharyngeal HPV related squamous cell carcinoma and the link between Scribble-NOS1AP and HPV, we sought to determine if Hippo signaling is implicated in such cancers. This study is the first to investigate Hippo signaling and Scribble-NOS1AP disruption in OPSCC.
P16, HPV positive OPSCC patient tissue was selected randomly from the samples in the Anatomical Pathology Department at the QEII Health Science Center. Any patient less than 18 year old, with HPV status uncertainty or non- oropharyngeal squamous cell carcinoma were excluded from the study. Tissue specimens were acquired from CO2 laser wide local resection of OPSCC. Malignant regions, as well as adjacent epithelia, were defined by an onsite histopathologic examination. A portion of the tissues were sectioned and used for hematoxylin and eosin (H&E) staining and immunofluorescence imaging. Sections (5 micron) of tissue were placed on OptiPlus Positive-Charged Barrier Slides.
All chemicals were purchased from Sigma, unless otherwise noted.
YAP is a mouse monoclonal antibody raised against recombinant human YAP (Santa Cruz, sc-101199); Scribble (H-300) (Santa Cruz – sc-28737) is a rabbit polyclonal antibody raised amino acids 1331-1630 mapping at the C-terminus of human Scribble; pLATS (Ser 909) Cell Signaling (#9157). Pan-NOS1AP and the pep-NOS1APc and GST-NOS1APc antibodies have previously been described [22, 23].
Cell culture and transfections
Human embryonic kidney HEK293T or MCF7 cells were grown at 37 °C with 5% carbon dioxide in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum (FBS), 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin.
Immunoprecipitations and Western blotting
Cell lines were homogenized in NP-40 lysis buffer (10% glycerol, 1% NP-40, 20 mM Tris [pH 8.0], 37.5 mM NaCl) containing 1 mM phenylmethylsulfonyl fluoride (PMSF), 10 μg/ml aprotinin, and 10 μg/ml leupeptin. Immunoprecipitation (IP) and Western blotting experiments were performed as previously reported . For analysis of YAP and phospho-YAP levels in HEK293T cells, protein concentration in whole-cell lysates was quantified using the Bradford assay , and lysates were prepared for immunoprecipitation (IP) and Western blotting.
Tissues were embedded in paraffin then cut in thin sections and preserved for further staining. The sections were then deparaffinized in xylene followed by rehydration through graded ethanol/water until rehydrated in phosphate buffered saline (PBS). Sections were then blocked in 5% normal goat serum containing 0.1% Triton X-100 in PBS. They were then incubated in blocking solution containing anti-YAP and anti-Scribble antibody overnight at 4°C. They were then washed 3 times in PBS followed by incubation with fluorescently labeled secondary antibodies for 1 h at room temperature. Sections were extensively washed in PBS, incubated in Hoechst 33342 (Life Science Technologies), suspended in PBS prior to mounting onto slides and imaging. All images were captured on a Leica DM6100 inverted microscope with appropriate filter sets using Intelligent Imaging Innovations (3i) software for acquisition. All post hoc imaging was done with Photoshop 6.0.
Thymidine incorporation studies
A thymidine incorporation assay was used to analyze serum-induced proliferation of YFP, YFP-NOS1APa or YFP-NOS1APc stable cell lines as described previously . The incorporation of 1 μCi/ml radioactive [methyl-3H] thymidine (Perkin-Elmer) into cellular DNA during a 15-min pulse time was quantified by liquid scintillation counting. The entire assay was repeated in two independent experiments, and the data are the averages from four independent replicates in each experiment.
NOS1AP and Scribble associate with the Hippo signaling component YAP
Distinct NOS1AP isoforms associate with phosphorylated YAP
NOS1AP regulates cellular proliferation
YAP accumulates in the nucleus of HPV-OPSCCs
The Hippo Pathway is a tumor suppressor pathway that was first described in Drosophila. It is involved in coordinating numerous proteins involved in diverse biological processes that have been implicated in terminal differentiation, and deregulation of this pathway leads to cancer . It has been shown in vitro that human Scribble is targeted for degradation by the high-risk HPV E6 proteins . More than 90% of endocervical cancers are HPV related . Nakagawa et al. was the first to describe a link between Scribble and HPV . Subsequent studies have linked higher-grade human endometrial lesions to higher degradation of Scribble protein . Recently, Hippo signaling has been linked to various cancers, and scribble has been shown to be an important mediator of Hippo signaling [25, 26]. In the current study, we sought to test if the human homologue of Scribble is involved in HPV positive OPSCC. We were able to demonstrate that Scribble  and its associating protein NOS1AP both precipitate YAP. Further, we found that different NOS1AP isoforms associate with non-phosphorylated YAP and phosphorylated YAP. The exogenous expression of both NOS1APa and NOS1APc affect cellular proliferation suggesting that both NOS1AP isoforms are involved in cellular growth. Finally, our preliminary results suggest a link between the Hippo pathway and the Scribble-NOS1AP axis in HPV related OPSCC. Notably, we found enrichment of YAP in the nucleus of malignant cells in HPV OPSCC, which was absent in benign adjacent cells (Fig. 4) implicating that YAP might provide a useful biomarker in HPV-OPSCC.
In cultured epithelial cells, the formation of cell-cell contacts is an important step in the terminal differentiation before the development of distinct apico-basal surfaces [10, 30]. Recently, the transcriptional co-activator YAP was implicated in this process . A number of groups have now shown that cell-cell contacts induce the activation of the LATS1/2 serine/threonine kinases that phosphorylate YAP [31–33]. Upon phosphorylation, YAP becomes restricted from the nucleus preventing the transcription of genes important in cell cycle progression [9.10]. A recent cervical cancer study showed that in high-grade cervical lesions nuclear levels of YAP are increased . Additionally, nuclear YAP levels are also increased in premalignant oral lesions . YAP has been found to be an independent prognostic marker for overall survival in liver cancer , and Xiao et al., showed that YAP can function as a predictive marker for cervical cancer . These considerations suggest that discerning to what extent Scribble, NOS1AP and the Hippo pathway intersect with HPV-mediated OPSCC will be an important goal for future work.
The HPV E6 protein is known to directly associate with Scribble and induce its degradation through proteasome mediated degradation; however, how this is linked to Hippo signaling activity remains unclear. Recent work has demonstrated that both the tumor suppressor functions of Scribble and the Hippo pathway are genetically linked to tissue growth regulation, and EMT transition [9, 37, 38]. We suggest one important avenue of research is to focus on the adaptor protein NOS1AP. Here we have shown that the NOS1AP isoforms associate with Hippo signaling components as well as with Scribble. Further, we show a differential association of NOS1AP isoforms with cytoplasmic localized and nuclear accumulated YAP. Similarly, we also show that Scribble associates with both differentially localized forms of YAP (Figs. 1 and 2). Whether these interactions with YAP are related to the distinct subcellular localizations of the different NOS1AP isoforms remains to be determined. Interestingly, in neurons endogenous NOS1APa has been reported in the nucleus where non-phosphorylated YAP is found . However, stable expression of NOS1APa is membrane localized in epithelial cell lines, and co-distributes with cytoplasmic YAP . Thus, whether YAP can associate with NOS1APa at cell-cell contacts in a non-phosphorylated or phosphorylated state remains to be explored. Despite the association of the different NOS1AP isoforms with distinct localized YAP pools, both NOS1APa and NOS1APc are capable of reducing cellular proliferation, consistent with previous work showing that NOS1APa functions as a tumor suppressor in breast cancer models . How NOS1AP functions to control Hippo signaling will be an important future focus in cancer biology.
The recent significant rise of HPV related OPSCC has led to a search for alternative pathways that might be more amenable to targeted therapies in future. It is also foreseeable that some of the involved proteins could be subjects for tumor diagnostics and prognosis. To date, we have observed this finding in one patient with HPV positive OPSCC with YAP localizing to the nucleus in tumor tissue. This work follows from another recent study showing that YAP levels are increased in HNSCC . Our current work extends this by demonstrating that in a HPV-OPSCC patient, YAP is localized in the nucleus, suggesting that Hippo signaling is possibly an important signaling pathway with relevance to HPV positive OPSCC, and to HNSCC in general. Further understanding of the signaling pathways utilized by the different NOS1AP isoforms may provide insight into the underlying biology of OPSCC, and may be an important biomarker in this context. As such, more patients with HPV-positive OPSCC are being recruited to extend our findings and to develop a sense of how the Scribble-NOS1AP-Hippo signaling cascade may differ according to cancer grade.
In this study the tumor suppressor protein Scribble associates with both YAP and phosphorylated YAP. Interestingly, the Scribble associating protein NOS1AP shows differential association with transcriptionally active and inactive YAP, indicating that distinct isoforms cooperate with the Hippo pathway to inhibit YAP. Further we show that YAP localizes to the nucleus in HPV positive OPSCC while in the pre-malignant tissues YAP is not enriched in the nucleus. Together our study implicates the potential importance of the Hippo pathway in OPSCC and points to the NOS1AP isoforms as potential biomarkers in this process.
Epithelial to mesenchymal transition
Hematoxylin and eosin
- Hoechst 33342:
NOS1AP Nitric Oxide Synthase 1 Adaptor Protein
Human papilloma virus
Large Tumor Suppressor
Oropharyngeal squamous cell carcinoma
Oral squamous cell carcinoma
Phosphate buffer solution
Yes Associated Protein
This project was funded by the Dalhousie Department of Surgery Seed Grant (RH and JPF) and an NSERC Discovery Grant (JPF). JPF acknowledges the Canadian Research Chair Program for funding during the course of this work.
Availability of data and materials
Presented in the main paper’s figures.
FA participated in obtaining ethical approval and fund, sample preparation, IHC specimen processing, bench-top analysis, data compilation and analysis, and drafted the manuscript. LC, MW and KM performed the immunoprecipitation assays and helped in data analysis. SM and CS performed the proliferation assays. MB was responsible for specimen preparation and was involved in study design. BAW was involved in writing the ethics and study design. MERG, MHR, JRBT and SMT assisted in subject recruitment and study design. JPF was involved in study design, specimen processing, bench-top analysis, obtaining funding and manuscript preparation. RDH was involved in study design, obtaining fund, subject recruitment and manuscript preparation. All authors read and approved the final manuscript.
The authors have no financial disclosure or conflicts of interest. This manuscript has not previously been published and is not currently under evaluation in any other peer-reviewed publication.
Consent for publication
Ethics approval and consent to participate
The Capital Health Research Ethics Board approved this study. Number: 1017718.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Avruch J, Zhou D, Bardeesy N. YAP oncogene overexpression supercharges colon cancer proliferation. Cell Cycle. 2012;11(6):1090–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Bilder D, Perrimon N. Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature. 2000;403(6770):676–80.View ArticlePubMedGoogle Scholar
- Dahlgren L, Dahlstrand HM, Lindquist D, Hogmo A, Bjornestal L, Lindholm J, et al. Human papillomavirus is more common in base of tongue than in mobile tongue cancer and is a favorable prognostic factor in base of tongue cancer patients. Int J Cancer. 2004;112(6):1015–9.View ArticlePubMedGoogle Scholar
- Enomoto M, Igaki T. Deciphering tumor-suppressor signaling in flies: genetic link between Scribble/Dlg/Lgl and the Hippo pathways. J Genet Genomics. 2011;38(10):461–70.View ArticlePubMedGoogle Scholar
- Halaoui R, McCaffrey L. Rewiring cell polarity signaling in cancer. Oncogene. 2015;34(8):939–50.View ArticlePubMedGoogle Scholar
- Hall CA, Wang R, Miao J, Oliva E, Shen X, Wheeler T, et al. Hippo pathway effector Yap is an ovarian cancer oncogene. Cancer Res. 2010;70(21):8517–25.View ArticlePubMedPubMed CentralGoogle Scholar
- He C, Lv X, Hua G, Lele SM, Remmenga S, Dong J, et al. YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression. Oncogene. 2015;34(50):6040–54.View ArticlePubMedPubMed CentralGoogle Scholar
- He C, Mao D, Hua G, Lv X, Chen X, Angeletti PC, et al. The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression. EMBO Mol Med. 2015;7(11):1426–49.View ArticlePubMedPubMed CentralGoogle Scholar
- Hergovich A. YAP-Hippo signalling downstream of leukemia inhibitory factor receptor: implications for breast cancer. Breast Cancer Res. 2012;14(6):326.View ArticlePubMedPubMed CentralGoogle Scholar
- Hiemer SE, Zhang L, Kartha VK, Packer TS, Almershed M, Noonan V, et al. A YAP/TAZ-Regulated Molecular Signature Is Associated with Oral Squamous Cell Carcinoma. Mol Cancer Res. 2015;13(6):957–68.View ArticlePubMedPubMed CentralGoogle Scholar
- Jones DL, Alani RM, Munger K. The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21Cip1-mediated inhibition of cdk2. Genes Dev. 1997;11(16):2101–11.View ArticlePubMedPubMed CentralGoogle Scholar
- Kang W, Tong JH, Chan AW, Lee TL, Lung RW, Leung PP, et al. Yes-associated protein 1 exhibits oncogenic property in gastric cancer and its nuclear accumulation associates with poor prognosis. Clin Cancer Res. 2011;17(8):2130–9.View ArticlePubMedGoogle Scholar
- Lee KP, Lee JH, Kim TS, Kim TH, Park HD, Byun JS, et al. The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. Proc Natl Acad Sci U S A. 2010;107(18):8248–53.View ArticlePubMedPubMed CentralGoogle Scholar
- Massimi P, Gammoh N, Thomas M, Banks L. HPV E6 specifically targets different cellular pools of its PDZ domain-containing tumour suppressor substrates for proteasome-mediated degradation. Oncogene. 2004;23(49):8033–9.View ArticlePubMedGoogle Scholar
- Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15(6):642–56.PubMedPubMed CentralGoogle Scholar
- Muramatsu T, Imoto I, Matsui T, Kozaki K, Haruki S, Sudol M, et al. YAP is a candidate oncogene for esophageal squamous cell carcinoma. Carcinogenesis. 2011;32(3):389–98.View ArticlePubMedGoogle Scholar
- Nakagawa S, Huibregtse JM. Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase. Mol Cell Biol. 2000;20(21):8244–53.View ArticlePubMedPubMed CentralGoogle Scholar
- Nakagawa S, Yano T, Nakagawa K, Takizawa S, Suzuki Y, Yasugi T, et al. Analysis of the expression and localisation of a LAP protein, human scribble, in the normal and neoplastic epithelium of uterine cervix. Br J Cancer. 2004;90(1):194–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Nichols AC, Dhaliwal SS, Palma DA, Basmaji J, Chapeskie C, Dowthwaite S, et al. Does HPV type affect outcome in oropharyngeal cancer? J Otolaryngol Head Neck Surg. 2013;42:9. 0216-42-9.View ArticlePubMedPubMed CentralGoogle Scholar
- St Guily JL, Clavel C, Okais C, Pretet JL, Beby-Defaux A, Agius G, et al. Human papillomavirus genotype distribution in tonsil cancers. Head Neck Oncol. 2011;3(1):6. 3284-3-6.View ArticlePubMedPubMed CentralGoogle Scholar
- Wang X, Su L, Ou Q. Yes-associated protein promotes tumour development in luminal epithelial derived breast cancer. Eur J Cancer. 2012;48(8):1227–34.View ArticlePubMedGoogle Scholar
- Richier L, Williton K, Clattenburg L, Colwill K, O'Brien M, Tsang C, Kolar A, Zinck N, Metalnikov P, Trimble WS, Krueger SR, Pawson T, Fawcett JP. NOS1AP associates with Scribble and regulates dendritic spine development. J Neurosci. 2010;30:4796–805. doi:10.1523/JNEUROSCI.3726-09.2010.View ArticlePubMedPubMed CentralGoogle Scholar
- Clattenburg L, Wigerius M, Qi J, Rainey JK, Rourke JL, Muruganandan S, Sinal CJ, Fawcett JP. NOS1AP Functionally Associates with YAP To Regulate Hippo Signaling. Mol Cell Biol. 2015;35(13):2265–77. doi:10.1128/MCB.00062-15.View ArticlePubMedPubMed CentralGoogle Scholar
- Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54. doi:10.1016/0003-2697(76)90527-3.View ArticlePubMedGoogle Scholar
- Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, et al. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 2011;147(4):759–72. doi:10.1016/j.cell.2011.09.048.View ArticlePubMedGoogle Scholar
- Mohseni M, Sun J, Lau A, Curtis S, Goldsmith J, et al. A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway. Nat Cell Biol. 2014;16(1):108–17. doi:10.1038/ncb2884.View ArticlePubMedGoogle Scholar
- Chen B, Zheng B, DeRan M, Jarugumilli GK, Fu J, Brooks YS, Wu X. ZDHHC7-mediated S-palmitoylation of Scribble regulates cell polarity. Nat Chem Biol. 2016. doi:10.1038/nchembio.2119.Google Scholar
- Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X. Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci. 2010;101(5):1279–85.View ArticlePubMedGoogle Scholar
- Ouyang Z, Zhan W, Dan L. hScrib, a human homolog of Drosophila neoplastic tumor suppressor, is involved in the progress of endometrial cancer. Oncol Res. 2010;18(11–12):593–9.PubMedGoogle Scholar
- Wei Z, Wang Y, Li Z, Yuan C, Zhang W, Wang D, et al. Overexpression of Hippo pathway effector TAZ in tongue squamous cell carcinoma: correlation with clinicopathological features and patients’ prognosis. J Oral Pathol Med. 2013;42(10):747–54.View ArticlePubMedGoogle Scholar
- Piccolo S, Dupont S, Cordenonsi M. The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev. 2014;94(4):1287–312. doi:10.1152/physrev.00005.2014.View ArticlePubMedGoogle Scholar
- Gumbiner BM, Kim NG. The Hippo-YAP signaling pathway and contact inhibition of growth. J Cell Sci. 2014;127(Pt 4):709–17. doi:10.1242/jcs.140103.View ArticlePubMedPubMed CentralGoogle Scholar
- Enderle L, McNeill H. Hippo gains weight: added insights and complexity to pathway control. Sci Signal. 2013;6(296):re7. doi:10.1126/scisignal.2004208.View ArticlePubMedGoogle Scholar
- Xiao H, Wu L, Zheng H, Li N, Wan H, Liang G, et al. Expression of Yes-associated protein in cervical squamous epithelium lesions. Int J Gynecol Cancer. 2014;24(9):1575–82.View ArticlePubMedGoogle Scholar
- Xu MZ, Yao TJ, Lee NP, Ng IO, Chan YT, Zender L, et al. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer. 2009;115(19):4576–85.View ArticlePubMedPubMed CentralGoogle Scholar
- Zhang X, George J, Deb S, Degoutin JL, Takano EA, Fox SB, et al. The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene. Oncogene. 2011;30(25):2810–22.View ArticlePubMedGoogle Scholar
- Rensburg HJJV, Yang X. The roles of the Hippo pathway in cancer metastasis. Cell Signal. 2016;28(11):1761–72. doi:10.1016/j.cellsig.2016.08.004.View ArticleGoogle Scholar
- Gandalovičová A, Vomastek T, Rosel D, Brábek J. Cell polarity signaling in the plasticity of cancer cell invasiveness. Oncotarget. 2016;25022–25049. doi:10.18632/oncotarget.7214.
- Shao B, Jiang J, Wu Q, Xu Y, Lv Q, et al. The nuclear localization of CAPON in hippocampus and cerebral cortex neurons after lipopolysaccharide stimulation. Neuroimmunomodulation. 2011;18(2):89–97. doi:10.1159/000320419.View ArticlePubMedGoogle Scholar
- Anastas JN, Biechele TL, Robitaille M, Muster J, Allison KH, et al. A protein complex of SCRIB, NOS1AP and VANGL1 regulates cell polarity and migration, and is associated with breast cancer progression. Oncogene. 2012;31(32):3696–708. doi:10.1038/onc.2011.528.View ArticlePubMedGoogle Scholar
- Ge L, Smail M, Meng W, Shyr Y, Ye F, et al. Yes-Associated Protein Expression in Head and Neck Squamous Cell Carcinoma Nodal Metastasis. PLoS One. 2011;6(11):e27529. doi:10.1371/journal.pone.0027529.View ArticlePubMedPubMed CentralGoogle Scholar