MAP4K Family Kinases Act in Parallel to MST1/2 to Activate LATS1/2 in the Hippo Pathway
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Characterization of a Novel MAP4K4-SASH1 Kinase Cascade Regulating Breast Cancer Tumorigenesis and Metastasis
Characterization of a Novel MAP4K4-SASH1 Kinase Cascade Regulating Breast Cancer Tumorigenesis and Metastasis Yadong Li Guizhou Medical University Daoqiu Wu The Aliated Hospital of Guizhou Medical University Jing Hou Guizhou Provincial People's Hospital Jing Zhang The Aliated Hospital of Guizhou Medical University Xing Zeng Chongqing Medical University Lian Chen Guizhou Medical University Xin Wan Guizhou Medical University Zhixiong Wu Guizhou medical university Jinyun Wang Guizhou Medical University Ke Wang Yongchuan Hospital of Chongqing Dan Yang The Aliated Hospital of Guizhou Medical University Hongyu Chen Guizhou Medical University Zexi Xu Guizhou medical university Lei Jia Guizhou Medical University Qianfan Liu Guizhou medical university Zhongshu Kuang Page 1/30 Fudan university Geli Jiang Chongqing Cancer Hospital Hui Zhang Chongqing Zhongshan Hospital Jie Luo Chongqing Cancer Hospital Wei Li Chongqing Cancer Hospital Xue Zou The Aliated Hospital of Guizhou Medical University Xiaohua Zeng Chongqing Cancer Hospital Ding'an Zhou ( [email protected] ) Guizhou Medical University https://orcid.org/0000-0002-6614-9321 Research Keywords: SASH1, MAP4K4, Tumorigenesis, Metastasis, Hormone-dependent breast cancers Posted Date: November 5th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-101160/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 2/30 Abstract Background: The SAM and SH3 domain containing protein 1(SASH1) was previously described as a candidate tumor-suppressor gene in breast cancer and colon cancer to mediate tumor metastasis and tumor growth. Howeverthe underlying mechanisms by which SASH1 implements breast cancer tumorigenesis and the question why SASH1 is downregulated in most solid cancers remain unexplored. -
The MAP4K4-STRIPAK Complex Promotes Growth and Tissue Invasion In
bioRxiv preprint doi: https://doi.org/10.1101/2021.05.07.442906; this version posted May 8, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 The MAP4K4-STRIPAK complex promotes growth and tissue invasion in 2 medulloblastoma 3 Jessica Migliavacca1, Buket Züllig1, Charles Capdeville1, Michael Grotzer2 and Martin Baumgartner1,* 4 1 Division of Oncology, Children’s Research Center, University Children’s Hospital Zürich, Zürich, 5 Switzerland 6 2 Division of Oncology, University Children’s Hospital Zürich, Zürich, Switzerland 7 8 *e-mail: [email protected] 9 10 Abstract 11 Proliferation and motility are mutually exclusive biological processes associated with cancer that depend 12 on precise control of upstream signaling pathways with overlapping functionalities. We find that STRN3 13 and STRN4 scaffold subunits of the STRIPAK complex interact with MAP4K4 for pathway regulation in 14 medulloblastoma. Disruption of the MAP4K4-STRIPAK complex impairs growth factor-induced 15 migration and tissue invasion and stalls YAP/TAZ target gene expression and oncogenic growth. The 16 migration promoting functions of the MAP4K4-STRIPAK complex involve the activation of novel PKCs 17 and the phosphorylation of the membrane targeting S157 residue of VASP through MAP4K4. The anti- 18 proliferative effect of complex disruption is associated with reduced YAP/TAZ target gene expression 19 and results in repressed tumor growth in the brain tissue. This dichotomous functionality of the STRIPAK 20 complex in migration and proliferation control acts through MAP4K4 regulation in tumor cells and 21 provides relevant mechanistic insights into novel tumorigenic functions of the STRIPAK complex in 22 medulloblastoma. -
Application of a MYC Degradation
SCIENCE SIGNALING | RESEARCH ARTICLE CANCER Copyright © 2019 The Authors, some rights reserved; Application of a MYC degradation screen identifies exclusive licensee American Association sensitivity to CDK9 inhibitors in KRAS-mutant for the Advancement of Science. No claim pancreatic cancer to original U.S. Devon R. Blake1, Angelina V. Vaseva2, Richard G. Hodge2, McKenzie P. Kline3, Thomas S. K. Gilbert1,4, Government Works Vikas Tyagi5, Daowei Huang5, Gabrielle C. Whiten5, Jacob E. Larson5, Xiaodong Wang2,5, Kenneth H. Pearce5, Laura E. Herring1,4, Lee M. Graves1,2,4, Stephen V. Frye2,5, Michael J. Emanuele1,2, Adrienne D. Cox1,2,6, Channing J. Der1,2* Stabilization of the MYC oncoprotein by KRAS signaling critically promotes the growth of pancreatic ductal adeno- carcinoma (PDAC). Thus, understanding how MYC protein stability is regulated may lead to effective therapies. Here, we used a previously developed, flow cytometry–based assay that screened a library of >800 protein kinase inhibitors and identified compounds that promoted either the stability or degradation of MYC in a KRAS-mutant PDAC cell line. We validated compounds that stabilized or destabilized MYC and then focused on one compound, Downloaded from UNC10112785, that induced the substantial loss of MYC protein in both two-dimensional (2D) and 3D cell cultures. We determined that this compound is a potent CDK9 inhibitor with a previously uncharacterized scaffold, caused MYC loss through both transcriptional and posttranslational mechanisms, and suppresses PDAC anchorage- dependent and anchorage-independent growth. We discovered that CDK9 enhanced MYC protein stability 62 through a previously unknown, KRAS-independent mechanism involving direct phosphorylation of MYC at Ser . -
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. -
Transcriptome Analysis of Human Diabetic Kidney Disease
ORIGINAL ARTICLE Transcriptome Analysis of Human Diabetic Kidney Disease Karolina I. Woroniecka,1 Ae Seo Deok Park,1 Davoud Mohtat,2 David B. Thomas,3 James M. Pullman,4 and Katalin Susztak1,5 OBJECTIVE—Diabetic kidney disease (DKD) is the single cases, mild and then moderate mesangial expansion can be leading cause of kidney failure in the U.S., for which a cure has observed. In general, diabetic kidney disease (DKD) is not yet been found. The aim of our study was to provide an considered a nonimmune-mediated degenerative disease unbiased catalog of gene-expression changes in human diabetic of the glomerulus; however, it has long been noted that kidney biopsy samples. complement and immunoglobulins sometimes can be de- — tected in diseased glomeruli, although their role and sig- RESEARCH DESIGN AND METHODS Affymetrix expression fi arrays were used to identify differentially regulated transcripts in ni cance is not clear (4). 44 microdissected human kidney samples. The DKD samples were The understanding of DKD has been challenged by multi- significant for their racial diversity and decreased glomerular ple issues. First, the diagnosis of DKD usually is made using filtration rate (~20–30 mL/min). Stringent statistical analysis, using clinical criteria, and kidney biopsy often is not performed. the Benjamini-Hochberg corrected two-tailed t test, was used to According to current clinical practice, the development of identify differentially expressed transcripts in control and diseased albuminuria in patients with diabetes is sufficient to make the glomeruli and tubuli. Two different Web-based algorithms were fi diagnosis of DKD (5). We do not understand the correlation used to de ne differentially regulated pathways. -
Non-Target Genes Regulate Mirnas-Mediated Migration Steering of Colorectal Carcinoma
Pathology & Oncology Research (2019) 25:559–566 https://doi.org/10.1007/s12253-018-0502-9 ORIGINAL ARTICLE Non-target Genes Regulate miRNAs-Mediated Migration Steering of Colorectal Carcinoma Sohair M. Salem1 & Ahmed R. Hamed2,3 & Alaaeldin G. Fayez1 & Ghada Nour Eldeen1,4 Received: 20 January 2018 /Accepted: 15 October 2018 /Published online: 25 October 2018 # Arányi Lajos Foundation 2018 Abstract MicroRNAs (miRNAs) trigger a two-layer regulatory network directly or through transcription factors and their co-regulators. Unlike miR-375, the role of miR-145 and miR-224 in inhibiting or driving cancer cell migration is controversial. This study is a step towards addressing the potential of miR-375, miR-145 and miR-224 expression modulation to inhibit colorectal carcinoma (CRC) cells migration in vitro through regulation of non-target genes VEGFA, TGFβ1, IGF1, CD105 and CD44. Transwell migration assay results revealed a significant subdue of migration ability of cells transfected with miR-375 and miR-145 mimics and miR-224 inhibitor. Real time PCR data showed that expression of VEGFA, TGFβ1, IGF1, CD105 and CD44 was downreg- ulated as a consequence of exogenous re-expression of miR-375 and inhibition of miR-224. On the other hand, ectopic expression of miR-145 did not affect VEGFA, TGFβ1 and CD44 expression, while it elevated CD105 and suppressed IGF1 expression. MAP4K4, a predicted target of miR-145, was validated as a target that could play a role in miR-145-mediated regulation of migration. At mRNA level, no change was observed in expression of MAP4K4 in cells with restored expression of miR-145, while western blotting analysis revealed a 25% reduction of protein level. -
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. -
The Hippo–YAP Pathway in Organ Size Control and Tumorigenesis: an Updated Version
Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW The Hippo–YAP pathway in organ size control and tumorigenesis: an updated version Bin Zhao,1 Li Li,1 Qunying Lei,2 and Kun-Liang Guan1,3 1Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA; 2Department of Biological Chemistry, School of Medicine, and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China The Hippo signaling pathway is gaining recognition as The Hippo pathway was named after the Drosophila an important player in both organ size control and Hippo kinase that was discovered using this approach. tumorigenesis, which are physiological and pathological Components of the Hippo pathway are highly conserved processes that share common cellular signaling mecha- in mammals (Fig. 1). Later genetic and biochemical studies nisms. Upon activation by stimuli such as high cell den- gradually shaped the current working model, in which the sity in cell culture, the Hippo pathway kinase cascade mammalian Mst1/2 kinase (Hippo homolog), complexed phosphorylates and inhibits the Yes-associated protein with a scaffold protein, Sav1, phosphorylates and activates (YAP)/TAZ transcription coactivators representing the the Lats1/2 kinase. Lats1/2 is also activated by another major signaling output of the pathway. Altered gene scaffold protein, Mob1 (Fig. 2). These four proteins are expression resulting from YAP/TAZ inhibition affects often referred to as the core components of the Hippo cell number by repressing cell proliferation and promot- pathway. At the upstream, several components have ing apoptosis, thereby limiting organ size.