The MST1/2-SAV1 Complex of the Hippo Pathway Promotes Ciliogenesis
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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. -
The Act of Controlling Adult Stem Cell Dynamics: Insights from Animal Models
biomolecules Review The Act of Controlling Adult Stem Cell Dynamics: Insights from Animal Models Meera Krishnan 1, Sahil Kumar 1, Luis Johnson Kangale 2,3 , Eric Ghigo 3,4 and Prasad Abnave 1,* 1 Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Gurgaon-Faridabad Ex-pressway, Faridabad 121001, India; [email protected] (M.K.); [email protected] (S.K.) 2 IRD, AP-HM, SSA, VITROME, Aix-Marseille University, 13385 Marseille, France; [email protected] 3 Institut Hospitalo Universitaire Méditerranée Infection, 13385 Marseille, France; [email protected] 4 TechnoJouvence, 13385 Marseille, France * Correspondence: [email protected] Abstract: Adult stem cells (ASCs) are the undifferentiated cells that possess self-renewal and differ- entiation abilities. They are present in all major organ systems of the body and are uniquely reserved there during development for tissue maintenance during homeostasis, injury, and infection. They do so by promptly modulating the dynamics of proliferation, differentiation, survival, and migration. Any imbalance in these processes may result in regeneration failure or developing cancer. Hence, the dynamics of these various behaviors of ASCs need to always be precisely controlled. Several genetic and epigenetic factors have been demonstrated to be involved in tightly regulating the proliferation, differentiation, and self-renewal of ASCs. Understanding these mechanisms is of great importance, given the role of stem cells in regenerative medicine. Investigations on various animal models have played a significant part in enriching our knowledge and giving In Vivo in-sight into such ASCs regulatory mechanisms. In this review, we have discussed the recent In Vivo studies demonstrating the role of various genetic factors in regulating dynamics of different ASCs viz. -
(12) Patent Application Publication (10) Pub. No.: US 2015/0023954 A1 Wu Et Al
US 2015 0023954A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0023954 A1 Wu et al. (43) Pub. Date: Jan. 22, 2015 (54) POTENTIATING ANTIBODY-INDUCED GOIN33/574 (2006.01) COMPLEMENT-MEDIATED CYTOTOXCITY A613 L/4745 (2006.01) VAPI3K INHIBITION A613 L/4375 (2006.01) (52) U.S. Cl. (71) Applicant: MEMORIAL SLOAN-KETTERING CPC ....... A6IK39/39558 (2013.01); A61 K3I/4745 CANCER CENTER, New York, NY (2013.01); A61 K39/00II (2013.01); A61 K (US) 39/385 (2013.01); A61K31/4375 (2013.01); A6IK3I/5377 (2013.01); A61K.39/39 (72) Inventors: Xiaohong Wu, Forest Hills, NY (US); (2013.01); GOIN33/57484 (2013.01); CI2O Wolfgang W. Scholz, San Diego, CA I/6886 (2013.01); A61 K 2039/505 (2013.01); (US); Govind Ragupathi, New York, C12O 2600/16 (2013.01); C12O 2600/106 NY (US); Philip O. Livingston, (2013.01); A61K 2039/545 (2013.01) Bluffton, SC (US) USPC .................. 424/133.1; 424/277.1; 424/193.1; 424f1 74.1436/5O1435/7.1 : 506/9:435/7.92: (21) Appl. No.: 14/387,153 s s 435/6.12. 436/94 (22) PCT Filed: Mar. 14, 2013 (57) ABSTRACT (86). PCT No.: PCT/US 13/31278 Methodologies and technologies for potentiating antibody S371 (c)(1), based cancer treatments by increasing complement-mediated (2) Date: Sep. 22, 2014 cell cytotoxicity are disclosed. Further provided are method O O ologies and technologies for overcoming ineffective treat Related U.S. Application Data ments correlated with and/or caused by sub-lytic levels of (60) Provisional application No. -
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. -
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). -
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. -
Mutual Regulation Between Hippo Signaling and Actin Cytoskeleton
Protein Cell 2013, 4(12): 904–910 DOI 10.1007/s13238-013-3084-z Protein & Cell REVIEW Mutual regulation between Hippo signaling and actin cytoskeleton Yurika Matsui1, Zhi-Chun Lai1,2,3 1 I ntercollege Graduate Degree Program in Cell and Developmental Biology, The Pennsylvania State University, University Park, PA 16802, USA 2 Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA 3 Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA Correspondence: [email protected] Received September 12, 2013 Accepted October 21, 2013 Cell & ABSTRACT core components are Hippo (Hpo, Mst1, and Mst2 in verte- brates), Salvador (Sav, Sav1, or WW45 in vertebrates), Warts Hippo signaling plays a crucial role in growth control and (Wts, Lats1, and Lats2 in vertebrates), and Mob as tumor sup- tumor suppression by regulating cell proliferation, apop- Protein pressor (Mats, MOBKL1a, and MOBKL1b in vertebrates). In tosis, and differentiation. How Hippo signaling is regulat- receiving a signal from the upstream regulators, Hpo (Mst1/2) ed has been under extensive investigation. Over the past phosphorylates Wts (Lats1/2) with the assistance of a scaf- three years, an increasing amount of data have supported folding protein, Sav (Sav1). This phosphorylation activates the a model of actin cytoskeleton blocking Hippo signaling kinase activity of Wts (Lats1/2), and along with its adaptor Mats activity to allow nuclear accumulation of a downstream (MOBKL1a/MOBKL1b), Wts (Lats1/2) phosphorylates Yorkie effector, Yki/Yap/Taz. On the other hand, Hippo signaling (Yki, Yap/Taz in vertebrates). 14-3-3 proteins interact with the negatively regulates actin cytoskeleton organization. -
Structural Basis for Autoactivation of Human Mst2 Kinase and Its Regulation by RASSF5
Structure Article Structural Basis for Autoactivation of Human Mst2 Kinase and Its Regulation by RASSF5 Lisheng Ni,1 Sheng Li,1,4 Jianzhong Yu,3 Jungki Min,1,5 Chad A. Brautigam,2 Diana R. Tomchick,2 Duojia Pan,3 and Xuelian Luo1,* 1Department of Pharmacology 2Department of Biophysics The University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA 3Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 4Present address: Biologics Department, Shanghai ChemPartner Co. Ltd., Shanghai 201203, China 5Present address: Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.str.2013.07.008 SUMMARY dor (Sav1), the NDR family kinases Lats1 and Lats2 (Lats1/2), and the adaptor protein Mob1. They form a central kinase The tumor-suppressive Hippo pathway controls cascade to transduce signals from cell-surface receptors tissue homeostasis through balancing cell prolifera- (Avruch et al., 2012; Hergovich, 2012). tion and apoptosis. Activation of the kinases Mst1 In the canonical Hippo kinase cascade, Mst1/2, in complex and Mst2 (Mst1/2) is a key upstream event in this with Sav1, phosphorylate and activate the Lats1/2-Mob1 com- pathway and remains poorly understood. Mst1/2 plexes, which then phosphorylate the transcriptional coactivator and their critical regulators RASSFs contain Yes-associated protein (YAP), a major downstream target of the Hippo pathway (Dong et al., 2007; Hao et al., 2008; Hong and Salvador/RASSF1A/Hippo (SARAH) domains that Guan, 2012; Huang et al., 2005; Zhao et al., 2007). -
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. -
SAV1 Monoclonal Antibody (M02), Clone 3B2
SAV1 monoclonal antibody (M02), clone 3B2 Catalog # : H00060485-M02 規格 : [ 100 ug ] List All Specification Application Image Product Mouse monoclonal antibody raised against a partial recombinant SAV1. Western Blot (Cell lysate) Description: Immunogen: SAV1 (NP_068590, 300 a.a. ~ 383 a.a) partial recombinant protein with GST tag. MW of the GST tag alone is 26 KDa. Sequence: HTAEIPDWLQVYARAPVKYDHILKWELFQLADLDTYQGMLKLLFMKELE QIVKMYEAYRQALLTELENRKQRQQWYAQQHGKNF enlarge Western Blot (Cell lysate) Host: Mouse Reactivity: Human Isotype: IgG2a Kappa Quality Control Antibody Reactive Against Recombinant Protein. enlarge Testing: Western Blot (Recombinant protein) Immunofluorescence enlarge Immunoprecipitation Western Blot detection against Immunogen (34.98 KDa) . Storage Buffer: In 1x PBS, pH 7.4 Storage Store at -20°C or lower. Aliquot to avoid repeated freezing and thawing. Instruction: enlarge MSDS: Download Sandwich ELISA (Recombinant protein) Datasheet: Download Publication Reference 1. Kidney-specific knockout of Sav1 in the mouse promotes hyper-proliferation of renal tubular epithelium through suppression of the Hippo pathway. Kai T, Tsukamoto Y, Hijiya N, Tokunaga A, Nakada C, Uchida T, Daa T, Iha H, enlarge Takahashi M, Nomura T, Sato F, Mimata H, Ikawa M, Seto M, Matsuura K, Moriyama M.J Pathol. 2016 Mar;239(1):97-108. ELISA 2. Hippo signaling mediates proliferation, invasiveness and metastatic potential of clear cell renal cell carcinoma. Schutte U, Bisht S, Heukamp LC, Kebschull M, Florin A, Haarmann J, Hoffmann P, Bendas G, Buettner R, Brossart P, Feldmann G.Translational Oncology Volume 7, Issue 2, April 2014, Pages 309–321 Page 1 of 4 2018/1/10 3. Screening of binding proteins that interact with human Salvador 1 in a human fetal liver cDNA library by the yeast two-hybrid system. -
Hippo Signaling Pathway in Liver and Pancreas: the Potential Drug Target for Tumor Therapy
http://informahealthcare.com/drt ISSN: 1061-186X (print), 1029-2330 (electronic) J Drug Target, Early Online: 1–9 ! 2014 Informa UK Ltd. DOI: 10.3109/1061186X.2014.983522 REVIEW ARTICLE Hippo signaling pathway in liver and pancreas: the potential drug target for tumor therapy Delin Kong*, Yicheng Zhao*, Tong Men, and Chun-Bo Teng College of life science, Northeast Forestry University, Harbin, China Abstract Keywords Cell behaviors, including proliferation, differentiation and apoptosis, are intricately controlled Cancer gene therapy, hepatic targeting, during organ development and tissue regeneration. In the past 9 years, the Hippo signaling in vitro model, tumor targeting pathway has been delineated to play critical roles in organ size control, tissue regeneration and tumorigenesis through regulating cell behaviors. In mammals, the core modules of the Hippo History signaling pathway include the MST1/2-LATS1/2 kinase cascade and the transcriptional co-activators YAP/TAZ. The activity of YAP/TAZ is suppressed by cytoplasmic retention due Received 5 September 2014 to phosphorylation in the canonical MST1/2-LATS1/2 kinase cascade-dependent manner or the Revised 21 October 2014 non-canonical MST1/2- and/or LATS1/2-independent manner. Hippo signaling pathway, which Accepted 29 October 2014 can be activated or inactivated by cell polarity, contact inhibition, mechanical stretch and Published online 3 December 2014 extracellular factors, has been demonstrated to be involved in development and tumorigenesis of liver and pancreas. In addition, we have summarized several small molecules currently available that can target Hippo-YAP pathway for potential treatment of hepatic and pancreatic cancers, providing clues for other YAP initiated cancers therapy as well.