The Hippo–YAP Pathway in Organ Size Control and Tumorigenesis: an Updated Version
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
MAP4K Family Kinases Act in Parallel to MST1/2 to Activate LATS1/2 in the Hippo Pathway
ARTICLE Received 19 Jun 2015 | Accepted 13 Aug 2015 | Published 5 Oct 2015 DOI: 10.1038/ncomms9357 OPEN MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway Zhipeng Meng1, Toshiro Moroishi1, Violaine Mottier-Pavie2, Steven W. Plouffe1, Carsten G. Hansen1, Audrey W. Hong1, Hyun Woo Park1, Jung-Soon Mo1, Wenqi Lu1, Shicong Lu1, Fabian Flores1, Fa-Xing Yu3, Georg Halder2 & Kun-Liang Guan1 The Hippo pathway plays a central role in tissue homoeostasis, and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include a kinase cascade of MST1/2 and LATS1/2 and the transcription co-activators YAP/TAZ. In response to stimulation, LATS1/2 phosphorylate and inhibit YAP/TAZ, the main effectors of the Hippo pathway. Accumulating evidence suggests that MST1/2 are not required for the regulation of YAP/TAZ. Here we show that deletion of LATS1/2 but not MST1/2 abolishes YAP/TAZ phosphorylation. We have identified MAP4K family members—Drosophila Happyhour homologues MAP4K1/2/3 and Misshapen homologues MAP4K4/6/7—as direct LATS1/2-activating kinases. Combined deletion of MAP4Ks and MST1/2, but neither alone, suppresses phosphorylation of LATS1/2 and YAP/TAZ in response to a wide range of signals. Our results demonstrate that MAP4Ks act in parallel to and are partially redundant with MST1/2 in the regulation of LATS1/2 and YAP/TAZ, and establish MAP4Ks as components of the expanded Hippo pathway. 1 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA. -
Dysfunctional Mechanotransduction Through the YAP/TAZ/Hippo Pathway As a Feature of Chronic Disease
cells Review Dysfunctional Mechanotransduction through the YAP/TAZ/Hippo Pathway as a Feature of Chronic Disease 1, 2, 2,3, 4 Mathias Cobbaut y, Simge Karagil y, Lucrezia Bruno y, Maria Del Carmen Diaz de la Loza , Francesca E Mackenzie 3, Michael Stolinski 2 and Ahmed Elbediwy 2,* 1 Protein Phosphorylation Lab, Francis Crick Institute, London NW1 1AT, UK; [email protected] 2 Department of Biomolecular Sciences, Kingston University, Kingston-upon-Thames KT1 2EE, UK; [email protected] (S.K.); [email protected] (L.B.); [email protected] (M.S.) 3 Department of Chemical and Pharmaceutical Sciences, Kingston University, Kingston-upon-Thames KT1 2EE, UK; [email protected] 4 Epithelial Biology Lab, Francis Crick Institute, London NW1 1AT, UK; [email protected] * Correspondence: [email protected] These authors contribute equally to this work. y Received: 30 November 2019; Accepted: 4 January 2020; Published: 8 January 2020 Abstract: In order to ascertain their external environment, cells and tissues have the capability to sense and process a variety of stresses, including stretching and compression forces. These mechanical forces, as experienced by cells and tissues, are then converted into biochemical signals within the cell, leading to a number of cellular mechanisms being activated, including proliferation, differentiation and migration. If the conversion of mechanical cues into biochemical signals is perturbed in any way, then this can be potentially implicated in chronic disease development and processes such as neurological disorders, cancer and obesity. This review will focus on how the interplay between mechanotransduction, cellular structure, metabolism and signalling cascades led by the Hippo-YAP/TAZ axis can lead to a number of chronic diseases and suggest how we can target various pathways in order to design therapeutic targets for these debilitating diseases and conditions. -
Genetic Variations Associated with Resistance to Doxorubicin and Paclitaxel in Breast Cancer
GENETIC VARIATIONS ASSOCIATED WITH RESISTANCE TO DOXORUBICIN AND PACLITAXEL IN BREAST CANCER by Irada Ibrahim-zada A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Laboratory Medicine and Pathobiology University of Toronto © Copyright by Irada Ibrahim-zada 2010 ii Genetic variations associated with resistance to doxorubicin and paclitaxel in breast cancer Irada Ibrahim-zada Doctor of Philosophy Department of Laboratory Medicine and Pathobiology University of Toronto 2010 Abstract Anthracycline- and taxane-based regimens have been the mainstay in treating breast cancer patients using chemotherapy. Yet, the genetic make-up of patients and their tumors may have a strong impact on tumor sensitivity to these agents and to treatment outcome. This study represents a new paradigm assimilating bioinformatic tools with in vitro model systems to discover novel genetic variations that may be associated with chemotherapy response in breast cancer. This innovative paradigm integrates drug response data for the NCI60 cell line panel with genome-wide Affymetrix SNP data in order to identify genetic variations associated with drug resistance. This genome wide association study has led to the discovery of 59 candidate loci that may play critical roles in breast tumor sensitivity to doxorubicin and paclitaxel. 16 of them were mapped within well-characterized genes (three related to doxorubicin and 13 to paclitaxel). Further in silico characterization and in vitro functional analysis validated their differential expression in resistant cancer cell lines treated with the drug of interest (over-expression of RORA and DSG1, and under-expression of FRMD6, SGCD, SNTG1, LPHN2 and DCT). iii Interestingly, three and six genes associated with doxorubicin and paclitaxel resistance, respectively, are involved in the apoptotic process in cells. -
MAPK and Hippo Signaling Pathways Crosstalk Via the RAF-1/MST-2 Interaction in Malignant Melanoma
ONCOLOGY REPORTS 38: 1199-1205, 2017 MAPK and Hippo signaling pathways crosstalk via the RAF-1/MST-2 interaction in malignant melanoma RUizheng Feng1, JUnSheng gong1, LinA WU2, LEI WANG3, BAoLin zhAng1, GANG LIANG2, hUixiA zheng2 and hong xiAo2 Departments of 1Plastic Surgery and 2Pathology, The First hospital of Shanxi Medical University, Taiyuan, Shanxi 030024; 3Department of Gerontology, Shanxi Dayi Hospital, Taiyuan, Shanxi 030000, P.R. China Received november 11, 2016; Accepted June 14, 2017 DOI: 10.3892/or.2017.5774 Abstract. The aim of the present study was to expound on sible for over 80% of all skin cancer-related deaths. In 2012, the interactions between the mitogen-activated protein kinase 232,000 new cases of melanoma and 55,000 melanoma-related (MAPK) and Hippo pathway members, and to further eluci- deaths were reported worldwide (1). Moreover, the incidence date the molecular mechanisms of melanoma tumorigenesis. of melanoma is increasing at a rate faster than that of any other Four melanoma cell lines (C32, HS695T, SK-MEL-28 and solid tumor, and is thought to be the highest in white-skinned A375) were used in the present study. Western blotting was people living at low latitudes (2). In its advanced stages, mela- used to assess the expression levels of the MAPK and Hippo noma is highly malignant, owing to its potential for distant pathway effector proteins: rapidly accelerated fibrosarcoma-1 metastasis (3), and an extremely low 5-year survival rate proto-oncogene, serine/threonine kinase (RAF-1); serine/thre- (5-16%) (4). Unfortunately, melanoma is refractory to conven- onine kinase 3 (STK3; also known as MST-2); yes-associated tional chemotherapeutics, thus, the treatment options for protein (YAP); and tafazzin (TAZ). -
Biallelic Alteration and Dysregulation of the Hippo Pathway in Mucinous Tubular and Spindle Cell Carcinoma of the Kidney
Published OnlineFirst September 7, 2016; DOI: 10.1158/2159-8290.CD-16-0267 RESEARCH BRIEF Biallelic Alteration and Dysregulation of the Hippo Pathway in Mucinous Tubular and Spindle Cell Carcinoma of the Kidney Rohit Mehra 1 , 2 , 3 , Pankaj Vats 1 , 3 , 4 , Marcin Cieslik 3 , Xuhong Cao 3 , 5 , Fengyun Su 3 , Sudhanshu Shukla 3 , Aaron M. Udager 1 , Rui Wang 3 , Jincheng Pan 6 , Katayoon Kasaian 3 , Robert Lonigro 3 , Javed Siddiqui 3 , Kumpati Premkumar 4 , Ganesh Palapattu 7 , Alon Weizer 2 , 7 , Khaled S. Hafez 7 , J. Stuart Wolf Jr 7 , Ankur R. Sangoi 8 , Kiril Trpkov 9 , Adeboye O. Osunkoya 10 , Ming Zhou 11 , Giovanna A. Giannico 12 , Jesse K. McKenney 13 , Saravana M. Dhanasekaran 1 , 3 , and Arul M. Chinnaiyan 1 , 2 , 3 , 5 , 7 ABSTRACT Mucinous tubular and spindle cell carcinoma (MTSCC) is a relatively rare subtype of renal cell carcinoma (RCC) with distinctive morphologic and cytogenetic fea- tures. Here, we carry out whole-exome and transcriptome sequencing of a multi-institutional cohort of MTSCC (n = 22). We demonstrate the presence of either biallelic loss of Hippo pathway tumor sup- pressor genes (TSG) and/or evidence of alteration of Hippo pathway genes in 85% of samples. PTPN14 (31%) and NF2 (22%) were the most commonly implicated Hippo pathway genes, whereas other genes such as SAV1 and HIPK2 were also involved in a mutually exclusive fashion. Mutations in the context of recurrent chromosomal losses amounted to biallelic alterations in these TSGs. As a readout of Hippo pathway inactivation, a majority of cases (90%) exhibited increased nuclear YAP1 protein expression. -
Targeting the Hippo Pathway in Prostate Cancer: What's New?
cancers Review Targeting the Hippo Pathway in Prostate Cancer: What’s New? Kelly Coffey Solid Tumour Target Discovery Laboratory, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; [email protected] Simple Summary: Prostate cancer is the most commonly diagnosed cancer in men in the UK, accounting for the deaths of over 11,000 men per year. A major problem in this disease are tumours which no longer respond to available treatments. Understanding how this occurs will reveal new ways to treat these patients. In this review, the latest findings regarding a particular group of cellular factors which make up a signalling network called the Hippo pathway will be described. Accumulating evidence suggests that this network contributes to prostate cancer progression and resistance to current treatments. Identifying how this pathway can be targeted with drugs is a promising area of research to improve the treatment of prostate cancer. Abstract: Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated for targeting the Hippo signalling pathway. Discovered in Drosophila melanogasta, the Hippo pathway plays a role in the regulation of organ size, proliferation, migration and invasion. In response to a variety of stimuli, including cell–cell contact, nutrients and stress, a kinase cascade is activated, which includes STK4/3 and LATS1/2 to inhibit the effector proteins YAP and its paralogue TAZ. -
Alternative Splicing Generates an Isoform of the Human Sef Gene with Altered Subcellular Localization and Specificity
Alternative splicing generates an isoform of the human Sef gene with altered subcellular localization and specificity Ella Preger*, Inbal Ziv*, Ariel Shabtay*, Ifat Sher*, Michael Tsang†, Igor B. Dawid†, Yael Altuvia‡, and Dina Ron*§ *Department of Biology, Technion–Israel Institute of Technology, Haifa 32000, Israel; †Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and ‡Department of Molecular Genetics and Biotechnology, Hebrew University–Hadassah Medical School, Jerusalem 91120, Israel Contributed by Igor B. Dawid, December 1, 2003 Receptor tyrosine kinases (RTKs) control a multitude of biological FGFs comprise a family of 22 structurally related polypeptide processes and are therefore subjected to multiple levels of regu- mitogens that control cell proliferation, differentiation, survival, lation. Negative feedback is one of the mechanisms that provide an and migration and play a key role in embryonic patterning effective means to control RTK-mediated signaling. Sef has re- (14–16). They signal via binding and activation of a family of cently been identified as a specific antagonist of fibroblast growth cell-surface tyrosine kinase receptors designated FGF receptors factor (FGF) signaling in zebrafish and subsequently in mouse and 1–4 (FGFR1–FGFR4) (17–20). Activated receptors trigger sev- human. Sef encodes a putative type I transmembrane protein that eral signal transduction cascades including the Ras͞MAPK and antagonizes the Ras͞mitogen-activated protein kinase pathway in the PI3-kinase pathway (15, 21). Depending on the cell type, all three species. Mouse Sef was also shown to inhibit the phos- FGF can also activate other MAPK pathways, such that leading phatidylinositol 3-kinase pathway. -
DLG5 Connects Cell Polarity and Hippo Signaling Protein Networks by Linking PAR-1 with MST1/2
Downloaded from genesdev.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2 Julian Kwan,1,2,7 Anna Sczaniecka,3,7 Emad Heidary Arash,1,4 Liem Nguyen,3 Chia-Chun Chen,3 Srdjana Ratkovic,2,5 Olga Klezovitch,3 Liliana Attisano,1,4 Helen McNeill,2,5 Andrew Emili,1,2 and Valeri Vasioukhin3,6 1Donnelly Centre for Cellular and Biomolecular Research, 2Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada; 3Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA; 4Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada; 5Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario M5G 1X5, Canada; 6Department of Pathology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98195, USA Disruption of apical–basal polarity is implicated in developmental disorders and cancer; however, the mechanisms connecting cell polarity proteins with intracellular signaling pathways are largely unknown. We determined previously that membrane-associated guanylate kinase (MAGUK) protein discs large homolog 5 (DLG5) functions in cell polarity and regulates cellular proliferation and differentiation via undefined mechanisms. We report here that DLG5 functions as an evolutionarily conserved scaffold and negative regulator of Hippo signaling, which controls organ size through the modulation of cell proliferation and differentiation. Affinity purification/mass spectrometry revealed a critical role of DLG5 in the formation of protein assemblies containing core Hippo kinases mammalian ste20 homologs 1/2 (MST1/2) and Par-1 polarity proteins microtubule affinity-regulating kinases 1/2/3 (MARK1/2/3). -
TABLE S1 Complete Overview of Protocols for Induction of Pscs Into
TABLE S1 Complete overview of protocols for induction of PSCs into renal lineages Ref 2D/ Cell type Protocol Days Growth factors Outcome Other analyses # 3D hiPSC, hESC, Collagen type I tx murine epidydymal fat pads,ex vivo 54 2D 8 Y27632, AA, CHIR, BMP7 IM miPSC, mESC Matrigel with murine fetal kidney hiPSC, hESC, Suspension,han tx murine epidydymal fat pads,ex vivo 54 2D 20 AA, CHIR, BMP7 IM miPSC, mESC ging drop with murine fetal kidney tx murine epidydymal fat pads,ex vivo 55 hiPSC, hESC Matrigel 2D 14 CHIR, TTNPB/AM580, Y27632 IM with murine fetal kidney Injury, tx murine epidydymal fat 57 hiPSC Suspension 2D 28 AA, CHIR, BMP7, TGF-β1, TTNPB, DMH1 NP pads,spinal cord assay Matrigel,membr 58 mNPC, hESC 3D 7 BPM7, FGF9, Heparin, Y27632, CHIR, LDN, BMP4, IGF1, IGF2 NP Clonal expansion ane filter iMatrix,spinal 59 hiPSC 3D 10 LIF, Y27632, FGF2/FGF9, TGF-α, DAPT, CHIR, BMP7 NP Clonal expansion cord assay iMatrix,spinal 59 murine NP 3D 8-19 LIF, Y27632, FGF2/FGF9, TGF- α, DAPT, CHIR, BMP7 NP Clonal expansion cord assay murine NP, Suspension, 60 3D 7-19 BMP7, FGF2, Heparin, Y27632, LIF NP Nephrotoxicity, injury model human NP membrane filter Suspension, Contractility and permeability assay, ex 61 hiPSC 2D 10 AA, BMP7, RA Pod gelatin vivo with murine fetal kidney Matrigel. 62 hiPSC, hESC fibronectin, 2D < 50 FGF2, AA, WNT3A, BMP4, BMP7, RA, FGF2, HGF or RA + VITD3 Pod collagen type I Matrigel, Contractility and uptake assay,ex vivo 63 hiPSC 2D 13 Y27632, CP21R7, BMP4, RA, BMP7, FGF9, VITD3 Pod collagen type I with murine fetal kidney Collagen -
SAV1 Promotes Hippo Kinase Activation Through Antagonizing the PP2A Phosphatase STRIPAK
RESEARCH ARTICLE SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK Sung Jun Bae1†, Lisheng Ni1†, Adam Osinski1, Diana R Tomchick2, Chad A Brautigam2,3, Xuelian Luo1,2* 1Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States; 2Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States; 3Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States Abstract The Hippo pathway controls tissue growth and homeostasis through a central MST- LATS kinase cascade. The scaffold protein SAV1 promotes the activation of this kinase cascade, but the molecular mechanisms remain unknown. Here, we discover SAV1-mediated inhibition of the PP2A complex STRIPAKSLMAP as a key mechanism of MST1/2 activation. SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. Two SAV1–MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. SAV1 directly binds to STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous activation of the Hippo pathway and alleviates the need for SAV1 in Hippo signaling. Thus, SAV1 promotes Hippo activation through counteracting the STRIPAKSLMAP PP2A *For correspondence: phosphatase complex. [email protected] DOI: https://doi.org/10.7554/eLife.30278.001 †These authors contributed equally to this work Competing interests: The Introduction authors declare that no The balance between cell division and death maintains tissue homeostasis of multicellular organisms. -
A Novel Fibroblast Growth Factor 1 Variant Reverses Nonalcoholic Fatty Liver Disease in Type 2 Diabetes
University of Louisville ThinkIR: The University of Louisville's Institutional Repository Electronic Theses and Dissertations 8-2018 A novel fibroblast growth factor 1 variant reverses nonalcoholic fatty liver disease in type 2 diabetes. Qian Lin University of Louisville Follow this and additional works at: https://ir.library.louisville.edu/etd Part of the Endocrine System Diseases Commons, and the Pharmacology Commons Recommended Citation Lin, Qian, "A novel fibroblast growth factor 1 variant reverses nonalcoholic fatty liver disease in type 2 diabetes." (2018). Electronic Theses and Dissertations. Paper 3016. https://doi.org/10.18297/etd/3016 This Doctoral Dissertation is brought to you for free and open access by ThinkIR: The University of Louisville's Institutional Repository. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of ThinkIR: The University of Louisville's Institutional Repository. This title appears here courtesy of the author, who has retained all other copyrights. For more information, please contact [email protected]. A NOVEL FIBROBLAST GROWTH FACTOR 1 VARIANT REVERSES NONALCOHOLIC FATTY LIVER DISEASE IN TYPE 2 DIABETES BY Qian Lin M.S. at Wenzhou Medical University, 2016 A Dissertation Submitted to the Faculty of the School of Medicine of the University of Louisville for the Degree of Doctor of Philosophy in Pharmacology and Toxicology Department of Pharmacology and Toxicology University of Louisville Louisville, Kentucky August 2018 A NOVEL FIBROBLAST GROWTH FACTOR 1 VARIANT REVERSES NONALCOHOLIC FATTY LIVER DISEASE IN TYPE 2 DIABETES BY Qian Lin Dissertation Approved on August 2, 2018 Dissertation Committee: Dr. Yi Tan Dr. Paul Epstein Dr. -
The Roles of Fgfs in the Early Development of Vertebrate Limbs
Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW The roles of FGFs in the early development of vertebrate limbs Gail R. Martin1 Department of Anatomy and Program in Developmental Biology, School of Medicine, University of California at San Francisco, San Francisco, California 94143–0452 USA ‘‘Fibroblast growth factor’’ (FGF) was first identified 25 tion of two closely related proteins—acidic FGF and ba- years ago as a mitogenic activity in pituitary extracts sic FGF (now designated FGF1 and FGF2, respectively). (Armelin 1973; Gospodarowicz 1974). This modest ob- With the advent of gene isolation techniques it became servation subsequently led to the identification of a large apparent that the Fgf1 and Fgf2 genes are members of a family of proteins that affect cell proliferation, differen- large family, now known to be comprised of at least 17 tiation, survival, and motility (for review, see Basilico genes, Fgf1–Fgf17, in mammals (see Coulier et al. 1997; and Moscatelli 1992; Baird 1994). Recently, evidence has McWhirter et al. 1997; Hoshikawa et al. 1998; Miyake been accumulating that specific members of the FGF 1998). At least five of these genes are expressed in the family function as key intercellular signaling molecules developing limb (see Table 1). The proteins encoded by in embryogenesis (for review, see Goldfarb 1996). Indeed, the 17 different FGF genes range from 155 to 268 amino it may be no exaggeration to say that, in conjunction acid residues in length, and each contains a conserved with the members of a small number of other signaling ‘‘core’’ sequence of ∼120 amino acids that confers a com- molecule families [including WNT (Parr and McMahon mon tertiary structure and the ability to bind heparin or 1994), Hedgehog (HH) (Hammerschmidt et al.