The Role of the C-Terminus Merlin in Its Tumor Suppressor Function Vinay Mandati
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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. -
Human T-Cell Lymphotropic Virus Type II Infection (Letter to the Editor)
HUMAN T-CELL L YMPHOTROPIC VIRUSES 1. Exposure Data 1.1 Structure, taxonomy and biology 1.1.1 Structure The structure of retroviruses is reviewed in the monograph on human immuno- deficiency viruses (HIV) in this volume. The human T-cell lymphotropic (T-cell Ieu- kaemia/lymphoma) viruses (HTL V) are enveloped viruses with a diameter of approxi- mately 80-100 nm (Figure 1). The HTLV virions contain two covalently bound genomic RNA strands, which are complexed with the viral enzymes reverse transcriptase (RT; with associated RNase H activity), integrase and protease and the capsid proteins. The outer part of the virions consists of a membrane-associated matrix protein and a lipid Iayer intersected by the envelope proteins (GeIderbIom, 1991). Figure 1. An electron micrograph of HTL V -1 virus Courtes y of Dr Bernard Kramarsky, Advanced Biotechnologies, Inc., Columbia, MD, USA 1.1.2 T axonomy and phylogeny Traditionally, retroviruses (family Retroviridae) have been cIassified according to a combination of criteria incIuding disease association, morphoIogy and cytopathic effects in vitro. On this basis three subfamiIies were defined. The oncoviruses (Greek, onkos = mass, swelling) consist of four morphological subtypes which are associated with tumours in naturally or experimentally infected animaIs, and non-oncogenic related viruses. The second group, the Ientiviruses (Latin, lentus = slow), cause a variety of diseases including immunodeficiency and wasting syndromes, usually after a long period -261- 262 IARC MONOGRAPHS VOLUME 67 of clinical latency. The third subfamily, the spumaviruses (Latin, spuma = foam), so called because of the characteristic 'foamy' appearance induced in infected cells in vitro, have not been conclusively 1inked to any disease. -
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. -
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. -
DDB1 Targets Chk1 to the Cul4 E3 Ligase Complex in Normal Cycling Cells and in Cells Experiencing Replication Stress
Published OnlineFirst March 10, 2009; DOI: 10.1158/0008-5472.CAN-08-3382 Research Article DDB1 Targets Chk1 to the Cul4 E3 Ligase Complex in Normal Cycling Cells and in Cells Experiencing Replication Stress Van Leung-Pineda,1 Jiwon Huh,1 and Helen Piwnica-Worms1,2,3 Departments of 1Cell Biology and Physiology and 2Internal Medicine and 3Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri Abstract protein FANCE (8, 10–12). Chk1 carries out its functions both in the The Chk1 protein kinase preserves genome integrity in normal nucleus and at the centrosome (13). Drugs that block Chk1 kinase proliferating cells and in cells experiencing replicative and activity or enhance its proteolysis by interfering with binding to genotoxic stress. Chk1 is currently being targeted in antican- heat shock protein 90 (HSP90) are currently being tested as cer regimens. Here, we identify damaged DNA-binding protein anticancer agents (14–17). 1 (DDB1) as a novel Chk1-interacting protein. DDB1 is part of Chk1 is regulated by reversible phosphorylation and by an E3 ligase complex that includes the cullin proteins Cul4A ubiquitin-mediated proteolysis. Under periods of replicative stress, and Cul4B. We report that Cul4A/DDB1 negatively regulates the ATRIP/ATR module binds to single-stranded DNA and, Chk1 stability in vivo. Chk1 associates with Cul4A/DDB1 together with Rad17 and the 9-1-1 complex, activates Chk1 in a Claspin-dependent manner (18–22). ATR directly phosphorylates during an unperturbed cell division cycle and both Chk1 317 345 phosphorylation and replication stress enhanced these inter- Chk1 on two COOH-terminal residues: Ser (S317) and Ser actions. -
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. -
Homo-Protacs for the Chemical Knockdown of Cereblon
Homo-PROTACs for the Chemical Knockdown of Cereblon Stefanie Lindner 60th ASH Annual Meeting and Exposition December 1, 2018 San Diego , CA IMiDs modulate substrate specificity of the CRBN E3 ligase Thalidomide Lenalidomide omalidomide IKZF1 Multiple IKZF3 Myeloma CRBN Proteasomal CK1α del(5q) MDS Neo- E3 ubiquitin ligase degradation substrate SALL4 Teratogenicity Ito et al., 2010, Science Krönke et al., 2014 Science Lu et al., 2014, Science Krönke et al., 2015, Nature Donovan et al., 2018, Elife Matyskiela et al., 2018, Nat Chem Biol. Proteolysis Targeting Chimeras (PROTACs) Bifunctional molecules for degradation of proteins of interest (POI) Thalidomide POI Lenalidomide ligand Pomalidomide linker POI IMiD CRBN PROTAC Sakamoto et. al, 2001, PNAS Schneekloth et. al, 2004, J Am Chem Soc. Lu et al., 2015, Chem Biol Winter et al., 2017, Mol Cell. Proteolysis Targeting Chimeras (PROTACs) Bifunctional molecules for degradation of proteins of interest (POI) POI IMiD CRBN Proteasomal PROTAC degradation Sakamoto et. al, 2001, PNAS Schneekloth et. al, 2004, J Am Chem Soc. Lu et al., 2015, Chem Biol Winter et al., 2017, Mol Cell. Homodimeric pomalidomide-based PROTACs Linker (size X) O O O HN O O NH O O HN NH O N N O Homo-bifunctional molecules O O Chemical Formula: C36H40N6O11 Molecular Weight: 732,75 Pomalidomide Pomalidomide Chemically CRBN Pom Pom CRBN induced CRBN knockdown Proteasomal POI = CRBN degradation Homodimeric pomalidomide-based PROTACs corresponding linker substructures No. of linear CRBN IKZF1 Linker linker atoms degradation degradation -
Activated Ezrin Controls MISP Levels to Ensure Correct Numa Polarization and Spindle Orientation Yvonne T
© 2018. Published by The Company of Biologists Ltd | Journal of Cell Science (2018) 131, jcs214544. doi:10.1242/jcs.214544 RESEARCH ARTICLE Activated ezrin controls MISP levels to ensure correct NuMA polarization and spindle orientation Yvonne T. Kschonsak1,2 and Ingrid Hoffmann1,* ABSTRACT misregulation in spindle orientation can result in disorganized tissue Correct spindle orientation is achieved through signaling pathways that morphology due to cell multi-layering, which could be associated provide a molecular link between the cell cortex and spindle with the earliest cancer developments (McCaffrey and Macara, microtubules in an F-actin-dependent manner. A conserved cortical 2011; Pease and Tirnauer, 2011). protein complex, composed of LGN (also known as GPSM2), NuMA The precise spindle position and orientation in the cell is achieved (also known as NUMA1) and dynein–dynactin, plays a key role in by signaling pathways generating pulling and pushing forces on the establishing proper spindle orientation. It has also been shown that the spindle, both externally or internally (Gönczy, 2002; Grill and actin-binding protein MISP and the ERM family, which are activated by Hyman, 2005; Théry et al., 2005; Fink et al., 2011). The longest lymphocyte-oriented kinase (LOK, also known as STK10) and Ste20- established player in spindle orientation is the conserved ternary α like kinase (SLK) (hereafter, SLK/LOK) in mitosis, regulate spindle complex, composed of G i, Leu-Gly-Asn repeat-enriched protein orientation. Here, we report that MISP functions downstream of the (LGN, also known as GPSM2) and nuclear mitotic apparatus ERM family member ezrin and upstream of NuMA to allow optimal (NuMA, also known as NUMA1) (Du et al., 2001; Du and Macara, α spindle positioning. -
Merlin Inhibits Wnt/Β-Catenin Signaling by Blocking LRP6 Phosphorylation
Cell Death and Differentiation (2016) 23, 1638–1647 & 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1350-9047/16 www.nature.com/cdd Merlin inhibits Wnt/β-catenin signaling by blocking LRP6 phosphorylation M Kim1,6, S Kim1,6, S-H Lee2,3,6, W Kim1, M-J Sohn4, H-S Kim5, J Kim*,2 and E-H Jho*,1 Merlin, encoded by the NF2 gene, is a tumor suppressor that acts by inhibiting mitogenic signaling and is mutated in Neurofibromatosis type II (NF2) disease, although its molecular mechanism is not fully understood. Here, we observed that Merlin inhibited Wnt/β-catenin signaling by blocking phosphorylation of LRP6, which is necessary for Wnt signal transduction, whereas mutated Merlin in NF2 patients did not. Treatment with Wnt3a enhanced phosphorylation of Ser518 in Merlin via activation of PAK1 in a PIP2-dependent manner. Phosphorylated Merlin dissociated from LRP6, allowing for phosphorylation of LRP6. Tissues from NF2 patients exhibited higher levels of β-catenin, and proliferation of RT4-D6P2T rat schwannoma cells was significantly reduced by treatment with chemical inhibitors of Wnt/β-catenin signaling. Taken together, our findings suggest that sustained activation of Wnt/β-catenin signaling due to abrogation of Merlin-mediated inhibition of LRP6 phosphorylation may be a cause of NF2 disease. Cell Death and Differentiation (2016) 23, 1638–1647; doi:10.1038/cdd.2016.54; published online 10 June 2016 Wnt/β-catenin signaling has essential roles in the regulation of β-catenin is then translocated into nuclei to activate -
Mir‑200B Regulates Breast Cancer Cell Proliferation and Invasion by Targeting Radixin
EXPERIMENTAL AND THERAPEUTIC MEDICINE 19: 2741-2750, 2020 miR‑200b regulates breast cancer cell proliferation and invasion by targeting radixin JIANFEN YUAN1, CHUNHONG XIAO2, HUIJUN LU1, HAIZHONG YU1, HONG HONG1, CHUNYAN GUO1 and ZHIMEI WU1 1Department of Clinical Laboratory, Nantong Traditional Chinese Medicine Hospital, Nantong, Jiangsu 226001; 2Department of Clinical Laboratory, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China Received December 7, 2018; Accepted October 15, 2019 DOI: 10.3892/etm.2020.8516 Abstract. Radixin is an important member of the miR-200b was lower in MDA-MB-231 cells compared with Ezrin-Radixin-Moesin protein family that is involved in cell that in MCF-7 cells. miR-200b mimic or siRNA-radixin invasion, metastasis and movement. microRNA (miR)-200b transfection downregulated the expression of radixin in is a well-studied microRNA associated with the develop- MDA-MB-231 cells and attenuated the invasive and prolifera- ment of multiple tumors. Previous bioinformatics analysis tive abilities of these cells. miR-200b-knockdown and radixin has demonstrated that miR-200b has a complementary overexpression were associated with enhanced cell invasion in binding site in the 3'-untranslated region of radixin mRNA. breast cancer. In conclusion, miR-200b regulates breast cancer The present study aimed to investigate the role of miR-200b cell proliferation and invasion by targeting radixin expression. in regulating radixin expression, cell proliferation and invasion in breast cancer. Breast cancer tissues at different Introduction Tumor-Node-Metastasis (TNM) stages were collected; breast tissues from patients with hyperplasia were used as a control. Breast cancer (BC) is one of the most common malignant miR-200b and radixin mRNA expression levels were tested tumors among women in the world that seriously threaten by reverse transcription-quantitative PCR. -
The CUL4A Ubiquitin Ligase Is a Potential Therapeutic Target in Skin Cancer and Other Malignancies
Chinese Journal of Cancer Review The CUL4A ubiquitin ligase is a potential therapeutic target in skin cancer and other malignancies Jeffrey Hannah1 and Peng-Bo Zhou1,2 Abstract Cullin 4A (CUL4A) is an E3 ubiquitin ligase that directly affects DNA repair and cell cycle progression by targeting substrates including damage-specific DNA-binding protein 2 (DDB2), xeroderma pigmentosum complementation group C (XPC), chromatin licensing and DNA replication factor 1 (Cdt1), and p21. Recent work from our laboratory has shown that Cul4a-deficient mice have greatly reduced rates of ultraviolet-induced skin carcinomas. On a cellular level, Cul4a-deficient cells have great capacity for DNA repair and demonstrate a slow rate of proliferation due primarily to increased expression of DDB2 and p21, respectively. This suggests that CUL4A promotes tumorigenesis (as well as accumulation of skin damage and subsequent premature aging) by limiting DNA repair activity and expediting S phase entry. In addition, CUL4A has been found to be up-regulated via gene amplification or overexpression in breast cancers, hepatocellular carcinomas, squamous cell carcinomas, adrenocortical carcinomas, childhood medulloblastomas, and malignant pleural mesotheliomas. Because of its oncogenic activity in skin cancer and up-regulation in other malignancies, CUL4A has arisen as a potential candidate for targeted therapeutic approaches. In this review, we outline the established functions of CUL4A and discuss the E3 ligase’s emergence as a potential driver of tumorigenesis. Key words Ubiquitination, cullins, DNA damage, cell cycle regulation, skin cancer, therapeutic targets For most cellular proteins, stability and degradation are scaffold, and one or multiple substrate-recruiting proteins at the regulated by the ubiquitin-proteosome system in which proteins are N-terminus[1,2]. -
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.