DOCSLIB.ORG

History and Progression of Fat Cadherins in Health and Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
History and Progression of Fat Cadherins in Health and Disease Journal name: OncoTargets and Therapy Article Designation: Review Year: 2016 Volume: 9 OncoTargets and Therapy Dovepress Running head verso: Zhang et al Running head recto: History and progression of Fat cadherins open access to scientific and medical research DOI: http://dx.doi.org/10.2147/OTT.S111176 Open Access Full Text Article REVIEW History and progression of Fat cadherins in health and disease Xiaofeng Zhang1,2,* Abstract: Intercellular adhesions are vital hubs for signaling pathways during multicellular Jinghua Liu3,* development and animal morphogenesis. In eukaryotes, under aberrant intracellular conditions, Xiao Liang1,2 cadherins are abnormally regulated, which can result in cellular pathologies such as carcinoma, Jiang Chen1,2 kidney disease, and autoimmune diseases. As a member of the Ca2+-dependent adhesion super- Junjie Hong1,2 family, Fat proteins were first described in the 1920s as an inheritable lethal mutant phenotype Libo Li1 in Drosophila, consisting of four member proteins, FAT1, FAT2, FAT3, and FAT4, all of which are highly conserved in structure. Functionally, FAT1 was found to regulate cell migration and Qiang He3 growth control through specific protein–protein interactions of its cytoplasmic tail. FAT2 and Xiujun Cai1,2 FAT3 are relatively less studied and are thought to participate in the development of human 1Department of General Surgery, cancer through a pathway similar to that of the Ena/VASP proteins. In contrast, FAT4 has 2Key Laboratory of Surgery of Zhejiang Province, Sir Run Run been widely studied in the context of biological functions and tumor mechanisms and has been For personal use only. Shaw Hospital, Zhejiang University, shown to regulate the planar cell polarity pathway, the Hippo signaling pathway, the canonical 3 Hangzhou, Zhejiang, Department of Wnt signaling cascade, and the expression of YAP1. Overall, Fat cadherins may be useful as Hepatobiliary Surgery, Linyi People’s Hospital, Linyi, Shandong, People’s emerging disease biomarkers and as novel therapeutic targets. Republic of China Keywords: Fat cadherins, FAT1, FAT2, FAT3, FAT4, CpG island, Hippo pathway, WNT *These authors contribute equally signaling to this work Introduction Cell–cell adhesions are important for the development of multicellular organisms and the process of animal morphogenesis. In eukaryotes, aberrant intracellular environ- ments can induce pathologic regulation of cadherins, leading to cellular pathologies such as carcinoma, kidney disease, and autoimmune diseases.1 OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 137.108.70.14 on 22-Jan-2020 As a member of the Ca2+-dependent adhesion superfamily, the cadherin family is divided into several subfamilies: classical cadherins, desmosomal cadherins, protocad- herins, Flamingo/Celsr, Dachsous (DS), and Fat cadherins. Each cadherin subfamily exhibits slightly divergent functions. For instance, classical cadherins function as links Correspondence: Xiujun Cai Department of General Surgery, Sir Run to the actin cytoskeleton, desmosomal cadherins are specific to the desmosome, proto- Run Shaw Hospital, Zhejiang University, cadherins are associated with stereocilia and somite epithelialization, and Flamingo/ Hangzhou 310016, Zhejiang, People’s 2 Republic of China Celsr and DS regulate the planar cell polarity (PCP) pathway. Tel/fax +86 571 8600 6605 Fat was first described in the 1920s in Drosophila as an inheritable lethal Email [email protected] mutant phenotype.2 Vertebrate Fat cadherin proteins are highly homologous with Qiang He Drosophila Fat proteins. Four members comprise this gene family: Fat1, Fat2, Fat3, Department of Hepatobiliary Surgery, and Fat4.1,3 Sequence analysis of the four vertebrate Fat cadherins, and in particular Linyi People’s Hospital, 27 East Jiefang Road, Linyi 276000, Shandong, People’s Fat4, shows that they are orthologous to Drosophila Fat. The Fat family is also Republic of China well conserved in structure and function, especially in human beings. In the past Tel/fax +86 539 807 8508 Email [email protected] two decades, the Fat family was demonstrated to be a tumor suppressor.1 In reality, submit your manuscript | www.dovepress.com OncoTargets and Therapy 2016:9 7337–7343 7337 Dovepress © 2016 Zhang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/OTT.S111176 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Zhang et al Dovepress owing to the extremely large size of mRNA transcripts and were found to interact with atrophin, a transcriptional co- encoded proteins, understanding the roles of Fat proteins repressor that also contributes to the function of Fat proteins has been challenging, and thus, the roles remain unknown. in the PCP pathway.8 While both Fat-Hippo and Fat-PCP signaling cascades have previously been shown to result in malformations, Fat1 tumorigenesis, and cancer metastasis, additional roles Structure and function remain to be elucidated.3–6 However, with the accumula- Fat1 is located on chromosome 4q34–35 and consists of tion of experimental data, technological advancements, 27 exons. It is the first Fat family member to be identified and and broader knowledge of disease mechanisms, the Fat the most frequently studied Fat protein. Fat1 was cloned in cadherin family is considered as an “emerging giant” of 1995 from a human T-leukemia cell line and has since been the cadherin superfamily. shown to be closely related to human diseases.1 Fat cadherins are single transmembrane receptors, distin- FAT1 interacts with related cadherins and Ena/VASP guished by 32–34 extracellular cadherin repeats of alternating proteins to regulate cell migration and actins dynamics. laminin G-like and EGF-like motifs. FAT1 and FAT4 contain Further studies have shown that FAT1 also binds to Ena/ 34 cadherin repeats, while FAT2 and FAT3 contain 32 and VASP proteins and regulates actin dynamics at both the 33 repeats, respectively. There are unique arrangements and cell–cell contact and ruffling edges.2,9 Furthermore, a TCF/ quantities of EGF-like and laminin G-like motifs that are LEF-binding site was discovered in the Fat1 promoter, specific for each member. Usually, the type of protein–protein 1,100 bp upstream of its transcriptional start site.6 interaction in the cytoplasmic domain of Fat cadherins differs Additionally, because the cytoplasmic region contains from that in its functional domains (Figure 1). various domains, FAT1 can interact directly with the Hippo– Furthermore, because of similarities in the structure of Wnt signaling cascade via the atrophin protein, HOMER-1 Fat proteins with other characterized proteins, Fat proteins to HOMER-3 protein, which competes with Ena for bind- may also act in similar signaling pathways.1–3 In a previous ing to FAT1 and β-cadherin.10–12 Finally, FAT1 was shown For personal use only. study on the common mutations in Fat genes of patients, non- to undergo alternative splicing in cancer cells undergoing synonymous somatic missense mutations did not influence epithelial-to-mesenchymal transition, where its cytoplasmic their level of protein expression.7 Additionally, Fat proteins tail was cleaved by the γ-secretase enzyme complex.13–15 &HOO +LSSR:QWVLJQDO PLJUDWLRQ SDWKZD\ $WURSKLQ 6FULEEOH OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 137.108.70.14 on 22-Jan-2020 <$3±7$= '6 3RODUL]HGFHOO GLYLVLRQ )UL]]OHG βFDWHQLQ (QD9$63 &HOOJURZWK 3&3 &HOOJURZWK $FWLQ &HOO DQGPLJUDWLRQ SRO\PHUL]DWLRQ PRYHPHQW Figure 1 Structure and function of the Fat cadherin family in human beings. Notes: The general molecular structure of Fat cadherins is illustrated in the schematic form based on the human sequence. All members have a predicted molecular weight in excess of 500 kDa. Their extracellular domain interacts with DS, and their cytoplasmic domain is related to proteins such as β-catenin, atrophin, and scribble. Abbreviation: DS, Dachsous. 7338 submit your manuscript | www.dovepress.com OncoTargets and Therapy 2016:9 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress History and progression of Fat cadherins Pathogenicity mechanism and signaling pathways cell carcinoma cells diminished the migration and number Analysis of adult human tissues shows Fat1 to be expressed in of filopodia.15 A Basic Local Alignment Search Tool search the development organs and at low levels in adult epithelia.16 of the human Fat2 coding sequence suggests that Fat2 Paradoxically, although it is a tumor suppressor, Fat1 was mRNA is expressed in gastric cancer, pancreatic cancer, downregulated in invasive breast cancer. On the contrary, ovarian cancer, and esophageal cancer. Furthermore, Fat2 Fat1 was upregulated in patients with leukemia and preB- expression was detected in hematological tissue, especially acute lymphoblastic leukemia.17,18 Thus, FAT1 may function in patients with 5q-syndrome. Mutations in Fat2 can also as a tumor suppressor and an oncogenic protein.19 Further- result in the
Load more

Recommended publications
  • Lats1/2 Regulate Yap/Taz to Control Nephron Progenitor Epithelialization and Inhibit Myofibroblast Formation
    BASIC RESEARCH www.jasn.org Lats1/2 Regulate Yap/Taz to Control Nephron Progenitor Epithelialization and Inhibit Myofibroblast Formation † † Helen McNeill* and Antoine Reginensi *Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; and †Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada ABSTRACT In the kidney, formation of the functional filtration units, the nephrons, is essential for postnatal life. During development, mesenchymal progenitors tightly regulate the balance between self-renewal and differentia- tion to give rise to all nephron epithelia. Here, we investigated the functions of the Hippo pathway serine/ threonine-protein kinases Lats1 and Lats2, which phosphorylate and inhibit the transcriptional coactivators Yap and Taz, in nephron progenitor cells. Genetic deletion of Lats1 and Lats2 in nephron progenitors of mice led to disruption of nephrogenesis, with an accumulation of spindle-shaped cells in both cortical and medullary regions of the kidney. Lineage-tracing experiments revealed that the cells that accumulated in the interstitium derived from nephron progenitor cells and expressed E-cadherin as well as vimentin, a myofibroblastic marker not usually detected after mesenchymal-to-epithelial transition. The accumulation of these interstitial cells associated with collagen deposition and ectopic expression of the myofibroblastic markers vimentin and a-smooth-muscle actin in developing kidneys. Although these myofibroblastic cells had high Yap and Taz accumulation in the nucleus concomitant with a loss of phosphorylated Yap, reduction of Yap and/or Taz expression levels completely rescued the Lats1/2 phenotype. Taken together, our results demonstrate that Lats1/2 kinases restrict Yap/Taz activities to promote nephron progenitor cell differentiation in the mamma- lian kidney.
    [Show full text]
  • Machine-Learning and Chemicogenomics Approach Defi Nes and Predicts Cross-Talk of Hippo and MAPK Pathways
    Published OnlineFirst November 18, 2020; DOI: 10.1158/2159-8290.CD-20-0706 RESEARCH ARTICLE Machine -Learning and Chemicogenomics Approach Defi nes and Predicts Cross-Talk of Hippo and MAPK Pathways Trang H. Pham 1 , Thijs J. Hagenbeek 1 , Ho-June Lee 1 , Jason Li 2 , Christopher M. Rose 3 , Eva Lin 1 , Mamie Yu 1 , Scott E. Martin1 , Robert Piskol 2 , Jennifer A. Lacap 4 , Deepak Sampath 4 , Victoria C. Pham 3 , Zora Modrusan 5 , Jennie R. Lill3 , Christiaan Klijn 2 , Shiva Malek 1 , Matthew T. Chang 2 , and Anwesha Dey 1 ABSTRACT Hippo pathway dysregulation occurs in multiple cancers through genetic and non- genetic alterations, resulting in translocation of YAP to the nucleus and activation of the TEAD family of transcription factors. Unlike other oncogenic pathways such as RAS, defi ning tumors that are Hippo pathway–dependent is far more complex due to the lack of hotspot genetic alterations. Here, we developed a machine-learning framework to identify a robust, cancer type–agnostic gene expression signature to quantitate Hippo pathway activity and cross-talk as well as predict YAP/TEAD dependency across cancers. Further, through chemical genetic interaction screens and multiomics analyses, we discover a direct interaction between MAPK signaling and TEAD stability such that knockdown of YAP combined with MEK inhibition results in robust inhibition of tumor cell growth in Hippo dysregulated tumors. This multifaceted approach underscores how computational models combined with experimental studies can inform precision medicine approaches including predictive diagnostics and combination strategies. SIGNIFICANCE: An integrated chemicogenomics strategy was developed to identify a lineage- independent signature for the Hippo pathway in cancers.
    [Show full text]
  • Ubiquitination‑Deubiquitination in the Hippo Signaling Pathway (Review)
    ONCOLOGY REPORTS 41: 1455-1475, 2019 Ubiquitination‑deubiquitination in the Hippo signaling pathway (Review) YANTING LIU and JUN DENG Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China Received April 3, 2018; Accepted September 17, 2018 DOI: 10.3892/or.2019.6956 Abstract. The Hippo signaling pathway is considered to be Ubiquitin modifications are involved in regulating various a tissue growth regulator and tumor suppressor pathway that physiological processes and are counteracted by deubiquiti- controls cell proliferation, differentiation, survival, regen- nation. Imbalanced ubiquitination-deubiquitination is closely eration and tissue homeostasis. Defects in Hippo kinases associated with tumor initiation and progression. Therefore, and hyperactivation of transcriptional co-activator with the examination of the specific association between the Hippo PDZ-binding motif and Yes-associated protein (YAP) may pathway and ubiquitination is of interest. The present study contribute to the development of different types of cancer. reviews the modulatory mechanism of ubiquitination-deubiq- The Hippo pathway is regulated in a variety of way, of which uitination in the Hippo signaling pathway, the recent progress ubiquitination is of considerable importance. Ubiquitination is in identifying therapeutic targets and strategies, and the future a crucial post‑translational protein modification in cancer cells directions in the field that may contribute to better tumor and is an applicable target for pharmacological intervention. diagnosis and treatment. Contents Correspondence to: Dr Jun Deng, Department of Oncology, The First Affiliated Hospital of Nanchang University, 17 Yong Wai 1. Introduction Zheng Street, Nanchang, Jiangxi 330006, P.R. China 2. Overview of the Hippo pathway E-mail: [email protected] 3.
    [Show full text]
  • The Legionella Kinase Legk7 Exploits the Hippo Pathway Scaffold Protein MOB1A for Allostery and Substrate Phosphorylation
    The Legionella kinase LegK7 exploits the Hippo pathway scaffold protein MOB1A for allostery and substrate phosphorylation Pei-Chung Leea,b,1, Ksenia Beyrakhovac,1, Caishuang Xuc, Michal T. Bonieckic, Mitchell H. Leea, Chisom J. Onub, Andrey M. Grishinc, Matthias P. Machnera,2, and Miroslaw Cyglerc,2 aDivision of Molecular and Cellular Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892; bDepartment of Biological Sciences, College of Liberal Arts and Sciences, Wayne State University, Detroit, MI 48202; and cDepartment of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N5E5, Canada Edited by Ralph R. Isberg, Tufts University School of Medicine, Boston, MA, and approved May 1, 2020 (received for review January 12, 2020) During infection, the bacterial pathogen Legionella pneumophila Active LATS1/2 phosphorylate the cotranscriptional regulator manipulates a variety of host cell signaling pathways, including YAP1 (yes-associated protein 1) and its homolog TAZ (tran- the Hippo pathway which controls cell proliferation and differen- scriptional coactivator with PDZ-binding motif). Phosphorylated tiation in eukaryotes. Our previous studies revealed that L. pneu- YAP1 and TAZ are prevented from entering the nucleus by being mophila encodes the effector kinase LegK7 which phosphorylates either sequestered in the cytosol through binding to 14-3-3 pro- MOB1A, a highly conserved scaffold protein of the Hippo path- teins or targeted for proteolytic degradation (6, 8). Consequently, way. Here, we show that MOB1A, in addition to being a substrate the main outcome of signal transduction along the Hippo pathway of LegK7, also functions as an allosteric activator of its kinase is changes in gene expression (6).
    [Show full text]
  • Inferring the Progression of Multifocal Liver Cancer from Spatial and Temporal Genomic Heterogeneity
    Inferring the progression of multifocal liver cancer from spatial and temporal genomic heterogeneity The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Shi, J., Q. Xing, M. Duan, Z. Wang, L. Yang, Y. Zhao, X. Wang, et al. 2016. “Inferring the progression of multifocal liver cancer from spatial and temporal genomic heterogeneity.” Oncotarget 7 (3): 2867-2877. doi:10.18632/oncotarget.6558. http:// dx.doi.org/10.18632/oncotarget.6558. Published Version doi:10.18632/oncotarget.6558 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:27320297 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 3 Inferring the progression of multifocal liver cancer from spatial and temporal genomic heterogeneity Jie-Yi Shi1,†, Qingfeng Xing2,†, Meng Duan1,†, Zhi-Chao Wang1,†, Liu-Xiao Yang1, Ying-Jun Zhao3, Xiao-Ying Wang1, Yun Liu2, Minghua Deng2, Zhen-Bin Ding1, Ai-Wu Ke1, Jian Zhou1,4, Jia Fan1,4, Ya Cao5, Jiping Wang6, Ruibin Xi2, Qiang Gao1 1 Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China 2School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, P. R. China 3 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shangai, P.
    [Show full text]
  • Essential Oil from Pinus Koraiensis Pinecones Inhibits Gastric Cancer Cells Via the HIPPO/YAP Signaling Pathway
    molecules Article Essential Oil from Pinus Koraiensis Pinecones Inhibits Gastric Cancer Cells via the HIPPO/YAP Signaling Pathway Yandong Zhang 1, Chao Xin 1, Junqiang Qiu 2 and Zhenyu Wang 1,* 1 Department of Food Science and Engineering, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150090, China; [email protected] (Y.Z.); [email protected] (C.X.) 2 Department of Inorganic Chemistry and Analytical Chemistry, School of Pharmacy, Hainan Medical University, Haikou 570100, China; [email protected] * Correspondence: [email protected] Received: 17 September 2019; Accepted: 22 October 2019; Published: 25 October 2019 Abstract: Pinecone is a traditional folk herb, which has been used in China for many years. In this paper, the essential oil from Pinus koraiensis pinecones (PEO) was obtained by hydrodistillation and 41 compounds were identified by gas chromatography–mass spectrometry (GC-MS), mainly including α-Pinene (40.91%), Limonene (24.82%), and β-Pinene (7.04%). The purpose of this study was to investigate the anti-tumor activity of PEO on MGC-803 cells and its mechanism. Anti-tumor experiments in vitro showed PEO could significantly inhibit the proliferation and migration of MGC-803 cells, and it also could arrest the cell cycle in the G2/M phase, decrease the mitochondrial membrane potential, and induce apoptosis. Finally, the effects of PEO on genes expression on MGC-803 cells were analyzed by RNA sequencing, and results showed that after treatment with PEO, 100 genes were up-regulated, and 57 genes were down-regulated. According to the KEGG pathway and GSEA, FAT4, STK3, LATS2, YAP1, and AJUBA were down-regulated, which were related to HIPPO signaling pathway.
    [Show full text]
  • The Role of the C-Terminus Merlin in Its Tumor Suppressor Function Vinay Mandati
    The role of the C-terminus Merlin in its tumor suppressor function Vinay Mandati To cite this version: Vinay Mandati. The role of the C-terminus Merlin in its tumor suppressor function. Agricultural sciences. Université Paris Sud - Paris XI, 2013. English. NNT : 2013PA112140. tel-01124131 HAL Id: tel-01124131 https://tel.archives-ouvertes.fr/tel-01124131 Submitted on 19 Mar 2015 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 1 TABLE OF CONTENTS Abbreviations ……………………………………………………………………………...... 8 Resume …………………………………………………………………………………… 10 Abstract …………………………………………………………………………………….. 11 1. Introduction ………………………………………………………………………………12 1.1 Neurofibromatoses ……………………………………………………………………….14 1.2 NF2 disease ………………………………………………………………………………15 1.3 The NF2 gene …………………………………………………………………………….17 1.4 Mutational spectrum of NF2 gene ………………………………………………………..18 1.5 NF2 in other cancers ……………………………………………………………………...20 2. ERM proteins and Merlin ……………………………………………………………….21 2.1 ERMs ……………………………………………………………………………………..21 2.1.1 Band 4.1 Proteins and ERMs …………………………………………………………...21 2.1.2 ERMs structure ………………………………………………………………………....23 2.1.3 Sub-cellular localization and tissue distribution of ERMs ……………………………..25 2.1.4 ERM proteins and their binding partners ……………………………………………….25 2.1.5 Assimilation of ERMs into signaling pathways ………………………………………...26 2.1.5. A. ERMs and Ras signaling …………………………………………………...26 2.1.5. B. ERMs in membrane transport ………………………………………………29 2.1.6 ERM functions in metastasis …………………………………………………………...30 2.1.7 Regulation of ERM proteins activity …………………………………………………...31 2.1.7.
    [Show full text]
  • Αe-Catenin Inhibits a Src–YAP1 Oncogenic Module That Couples Tyrosine Kinases and the Effector of Hippo Signaling Pathway
    Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press αE-catenin inhibits a Src–YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway Peng Li,1,4 Mark R. Silvis,1,4 Yuchi Honaker,1,4 Wen-Hui Lien,1,3 Sarah T. Arron,2 and Valeri Vasioukhin1 1Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA; 2Department of Dermatology, University of California at San Fricisco, San Francisco, California, 94143, USA Cell–cell adhesion protein αE-catenin inhibits skin squamous cell carcinoma (SCC) development; however, the mechanisms responsible for this function are not completely understood. We report here that αE-catenin inhibits β4 integrin-mediated activation of SRC tyrosine kinase. SRC is the first discovered oncogene, but the protein substrate critical for SRC-mediated transformation has not been identified. We found that YAP1, the pivotal effector of the Hippo signaling pathway, is a direct SRC phosphorylation target, and YAP1 phosphorylation at three sites in its transcription activation domain is necessary for SRC–YAP1-mediated transformation. We uncovered a marked in- crease in this YAP1 phosphorylation in human and mouse SCC tumors with low/negative expression of αE-catenin. We demonstrate that the tumor suppressor function of αE-catenin involves negative regulation of the β4 integrin– SRC signaling pathway and that SRC-mediated phosphorylation and activation of YAP1 are an alternative to the canonical Hippo signaling pathway that directly connect oncogenic tyrosine kinase signaling with YAP1. [Keywords: αE-catenin; SRC; YAP1; SCC; keratinocytes; skin] Supplemental material is available for this article.
    [Show full text]
  • YAP1 Monoclonal Antibody
    For Research Use Only YAP1 Monoclonal antibody Catalog Number:66900-1-Ig Featured Product 10 Publications www.ptgcn.com Catalog Number: GenBank Accession Number: CloneNo.: Basic Information 66900-1-Ig BC038235 3A7A9 Size: GeneID (NCBI): Recommended Dilutions: 1000 μg/ml 10413 WB 1:2000-1:8000 Source: Full Name: IHC 1:1000-1:4000 Mouse Yes-associated protein 1, 65kDa IF 1:50-1:500 Isotype: Calculated MW: IgG1 504 aa, 54 kDa Purification Method: Observed MW: Protein G purification 70 kDa Immunogen Catalog Number: AG28194 Applications Tested Applications: Positive Controls: IF, IHC, WB,ELISA WB : HeLa cells; HSC-T6 cells, NIH/3T3 cells, MCF-7 Cited Applications: cells, HUVEC cells IF, IHC, WB IHC : human lung cancer tissue; human colon cancer Species Specificity: tissue, human liver cancer tissue, human ovary tumor Human, mouse, rat tissue Cited Species: IF : HepG2 cells; human, mouse, rat Note-IHC: suggested antigen retrieval with TE buffer pH 9.0; (*) Alternatively, antigen retrieval may be performed with citrate buffer pH 6.0 Yes-associated protein 1 (YAP1) is a transcriptional regulator which can act both as a coactivator and a corepressor Background Information and is the critical downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ.
    [Show full text]
  • YAP OFF, YAP on by Michael Leviten, Senior Writer Vivace Therapeutics Inc
    REPRINT FROM NOVEMBER 16, 2017 EMERGING COMPANY PROFILE YAP OFF, YAP ON By Michael Leviten, Senior Writer Vivace Therapeutics Inc. exploits opposite angles of the Hippo-YAP pathway, with first-in-class inhibitors that turn VIVACE THERAPEUTICS INC., San Mateo, Calif. it off in cancers with activating mutations and activators Technology: Hippo-YAP pathway modulators as targeted therapies or that turn it on to enhance tumor immunogenicity in other immuno-oncology agents Disease focus: Cancer cancers. The newco emerged from stealth mode this summer Clinical status: Preclinical after closing a $25 million Series B led by China-based Founded: 2015 by Sofie Qiao, Tim Shannon, Edward Hu, Kun-Liang Guan, Bin Cenova Capital. Liu, Sheng Ding The Hippo-YAP pathway regulates cell growth and survival. University collaborators: University of California San Diego, University of Under normal conditions, Hippo signaling phosphorylates California San Francisco Corporate partners: None YAP1 and silences it. But under cellular stress, G-protein Number of employees: Five signaling dephosphorylates YAP1, triggering its Funds raised: $40 million translocation to the nucleus where it induces expression of Investors: Canaan Partners, WuXi Healthcare Ventures, Mission Bay Capital, survival genes. Cenova Capital and Sequoia Capital China Several cancers co-opt the pathway for survival and proliferation. CEO: Sofie Qiao About 85% of uveal melanomas have activating mutations in Patents: None issued the G-proteins GαQ and GNA11, 70% of mesotheliomas have activated YAP1, and YAP1 gene amplifications occur in about 25% of all lung, cervical and thyroid cancers. ReliTrexed, an injectable formulation of pemetrexed, for Because the pathway has been difficult to drug, Vivace took a mesothelioma, with at least 30 more compounds in the target-agnostic approach in undisclosed cancer cell lines to clinic.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • Characterization of a Dchs1 Mutant Mouse Reveals Requirements For
    RESEARCH ARTICLE 947 Development 138, 947-957 (2011) doi:10.1242/dev.057166 © 2011. Published by The Company of Biologists Ltd Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development Yaopan Mao1, Joanna Mulvaney2, Sana Zakaria2, Tian Yu2,3, Katherine Malanga Morgan1, Steve Allen4, M. Albert Basson2,3, Philippa Francis-West2,*,† and Kenneth D. Irvine1,*,† SUMMARY The Drosophila Dachsous and Fat proteins function as ligand and receptor, respectively, for an intercellular signaling pathway that regulates Hippo signaling and planar cell polarity. Although gene-targeted mutations in two mammalian Fat genes have been described, whether mammals have a Fat signaling pathway equivalent to that in Drosophila, and what its biological functions might be, have remained unclear. Here, we describe a gene-targeted mutation in a murine Dachsous homolog, Dchs1. Analysis of the phenotypes of Dchs1 mutant mice and comparisons with Fat4 mutant mice identify requirements for these genes in multiple organs, including the ear, kidney, skeleton, intestine, heart and lung. Dchs1 and Fat4 single mutants and Dchs1 Fat4 double mutants have similar phenotypes throughout the body. In some cases, these phenotypes suggest that Dchs1-Fat4 signaling influences planar cell polarity. In addition to the appearance of cysts in newborn kidneys, we also identify and characterize a requirement for Dchs1 and Fat4 in growth, branching and cell survival during early kidney development. Dchs1 and Fat4 are predominantly expressed in mesenchymal cells in multiple organs, and mutation of either gene increases protein staining for the other. Our analysis implies that Dchs1 and Fat4 function as a ligand-receptor pair during murine development, and identifies novel requirements for Dchs1-Fat4 signaling in multiple organs.
    [Show full text]