EPLIN mediates linkage of the cadherin catenin complex to F-actin and stabilizes the circumferential actin belt.
AuthorsAbe K, Takeichi M,
JournalProc Natl Acad Sci U S A
PubMed ID18093941
'The cadherin-catenin complex is the major machinery for cell-cell adhesion in many animal species. This complex in general associates with actin fibers at its cytoplasmic side, organizing the adherens junction (AJ). In epithelial cells, the AJ encircles the cells near their apical surface and forms the "zonula adherens" or "adhesion ... More
Cytohesins are cytoplasmic ErbB receptor activators.
AuthorsBill A, Schmitz A, Albertoni B, Song JN, Heukamp LC, Walrafen D, Thorwirth F, Verveer PJ, Zimmer S, Meffert L, Schreiber A, Chatterjee S, Thomas RK, Ullrich RT, Lang T, Famulok M,
JournalCell
PubMed ID20946980
'Signaling by ErbB receptors requires the activation of their cytoplasmic kinase domains, which is initiated by ligand binding to the receptor ectodomains. Cytoplasmic factors contributing to the activation are unknown. Here we identify members of the cytohesin protein family as such factors. Cytohesin inhibition decreased ErbB receptor autophosphorylation and signaling, ... More
The spectrin cytoskeleton influences the surface expression and activation of human transient receptor potential channel 4 channels.
AuthorsOdell AF, Van Helden DF, Scott JL,
JournalJ Biol Chem
PubMed ID18048348
'Despite over a decade of research, only recently have the mechanisms governing transient receptor potential channel (TRPC) channel function begun to emerge, with an essential role for accessory proteins in this process. We previously identified a tyrosine phosphorylation event as critical in the plasma membrane translocation and activation of hTRPC4 ... More
Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi.
'BRAF and NRAS are common targets for somatic mutations in benign and malignant neoplasms that arise from melanocytes situated in epithelial structures, and lead to constitutive activation of the mitogen-activated protein (MAP) kinase pathway. However, BRAF and NRAS mutations are absent in a number of other melanocytic neoplasms in which ... More
Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks.
AuthorsGalanty Y, Belotserkovskaya R, Coates J, Polo S, Miller KM, Jackson SP,
JournalNature
PubMed ID20016603
'DNA double-strand breaks (DSBs) are highly cytotoxic lesions that are generated by ionizing radiation and various DNA-damaging chemicals. Following DSB formation, cells activate the DNA-damage response (DDR) protein kinases ATM, ATR and DNA-PK (also known as PRKDC). These then trigger histone H2AX (also known as H2AFX) phosphorylation and the accumulation ... More
Ars2 links the nuclear cap-binding complex to RNA interference and cell proliferation.
AuthorsGruber JJ, Zatechka DS, Sabin LR, Yong J, Lum JJ, Kong M, Zong WX, Zhang Z, Lau CK, Rawlings J, Cherry S, Ihle JN, Dreyfuss G, Thompson CB,
JournalCell
PubMed ID19632182
'Here we identify a component of the nuclear RNA cap-binding complex (CBC), Ars2, that is important for miRNA biogenesis and critical for cell proliferation. Unlike other components of the CBC, Ars2 expression is linked to the proliferative state of the cell. Deletion of Ars2 is developmentally lethal, and deletion in ... More
Resistance to therapy caused by intragenic deletion in BRCA2.
AuthorsEdwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, Boyd J, Reis-Filho JS, Ashworth A,
JournalNature
PubMed ID18264088
'Cells with loss of BRCA2 function are defective in homologous recombination (HR) and are highly sensitive to inhibitors of poly(ADP-ribose) polymerase (PARP), which provides the basis for a new therapeutic approach. Here we show that resistance to PARP inhibition can be acquired by deletion of a mutation in BRCA2. We ... More
MKKS Is a Centrosome-shuttling Protein Degraded by Disease-causing Mutations via CHIP-mediated Ubiquitination.
AuthorsHirayama S, Yamazaki Y, Kitamura A, Oda Y, Morito D, Okawa K, Kimura H, Cyr DM, Kubota H, Nagata K,
JournalMol Biol Cell
PubMed ID18094050
'McKusick-Kaufman syndrome (MKKS) is a recessively inherited human genetic disease characterized by several developmental anomalies. Mutations in the MKKS gene also cause Bardet-Biedl syndrome (BBS), a genetically heterogeneous disorder with pleiotropic symptoms. However, little is known about how MKKS mutations lead to disease. Here, we show that disease-causing mutants of ... More
A novel CpG-free vertebrate insulator silences the testis-specific SP-10 gene in somatic tissues: role for TDP-43 in insulator function.
AuthorsAbhyankar MM, Urekar C, Reddi PP,
JournalJ Biol Chem
PubMed ID17932037
'Regulation of cell type-specific gene transcription is central to cellular differentiation and development. During spermatogenesis, a number of testis-specific genes are expressed in a precise spatiotemporal order. How these genes remain silent in the somatic tissues is not well understood. Our previous studies using the round spermatid-specific mouse SP-10 gene, ... More
ATR pathway is the primary pathway for activating G2/M checkpoint induction after re-replication.
AuthorsLin JJ, Dutta A,
JournalJ Biol Chem
PubMed ID17716975
'DNA replication is tightly controlled to ensure accurate chromosome duplication and segregation in each cell cycle. Inactivation of Geminin, an inhibitor of origin licensing, leads to re-replication in human tumor cells within the same cell cycle and triggers a G(2)/M checkpoint. We find that the primary pathway to signal that ... More
Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome.
AuthorsMinegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, Metin A, Karasuyama H,
JournalNature
PubMed ID17676033
'Hyper-immunoglobulin E syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with disproportionately milder inflammatory responses, referred to as cold abscesses, and skeletal abnormalities. Although some cases of familial HIES with autosomal dominant or recessive inheritance have been ... More
Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles.
AuthorsDavis ME, Zuckerman JE, Choi CH, Seligson D, Tolcher A, Alabi CA, Yen Y, Heidel JD, Ribas A,
JournalNature
PubMed ID20305636
'Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans, and the potential use of RNAi for human therapy has been demonstrated by the finding ... More
STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling.
AuthorsIshikawa H, Barber GN,
JournalNature
PubMed ID18724357
'The cellular innate immune system is essential for recognizing pathogen infection and for establishing effective host defence. But critical molecular determinants responsible for facilitating an appropriate immune response-following infection with DNA and RNA viruses, for example-remain to be identified. Here we report the identification, following expression cloning, of a molecule ... More
ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks.
'DNA double-strand breaks (DSBs) initiate extensive local and global alterations in chromatin structure, many of which depend on the ATM kinase. Histone H2A ubiquitylation (uH2A) on chromatin surrounding DSBs is one example, thought to be important for recruitment of repair proteins. uH2A is also implicated in transcriptional repression; an intriguing ... More
Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP.
AuthorsHafner M, Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P, Rothballer A, Ascano M, Jungkamp AC, Munschauer M, Ulrich A, Wardle GS, Dewell S, Zavolan M, Tuschl T,
JournalCell
PubMed ID20371350
'RNA transcripts are subject to posttranscriptional gene regulation involving hundreds of RNA-binding proteins (RBPs) and microRNA-containing ribonucleoprotein complexes (miRNPs) expressed in a cell-type dependent fashion. We developed a cell-based crosslinking approach to determine at high resolution and transcriptome-wide the binding sites of cellular RBPs and miRNPs. The crosslinked sites are ... More
Structural basis of the 9-fold symmetry of centrioles.
AuthorsKitagawa D, Vakonakis I, Olieric N, Hilbert M, Keller D, Olieric V, Bortfeld M, Erat MC, Flückiger I, Gönczy P, Steinmetz MO,
JournalCell
PubMed ID21277013
'The centriole, and the related basal body, is an ancient organelle characterized by a universal 9-fold radial symmetry and is critical for generating cilia, flagella, and centrosomes. The mechanisms directing centriole formation are incompletely understood and represent a fundamental open question in biology. Here, we demonstrate that the centriolar protein ... More
Nucleosome-interacting proteins regulated by DNA and histone methylation.
AuthorsBartke T, Vermeulen M, Xhemalce B, Robson SC, Mann M, Kouzarides T,
JournalCell
PubMed ID21029866
Modifications on histones or on DNA recruit proteins that regulate chromatin function. Here, we use nucleosomes methylated on DNA and on histone H3 in an affinity assay, in conjunction with a SILAC-based proteomic analysis, to identify ... More
Treslin collaborates with TopBP1 in triggering the initiation of DNA replication.
AuthorsKumagai A, Shevchenko A, Shevchenko A, Dunphy WG,
JournalCell
PubMed ID20116089
TopBP1 has important roles in both DNA replication and checkpoint regulation in vertebrates. We have identified a protein called Treslin that associates with TopBP1 in Xenopus egg extracts. Depletion of Treslin from egg extracts strongly inhibits chromosomal DNA replication. Binding of Treslin to chromatin in egg extracts occurs independently of ... More
The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia.
AuthorsJin H, White SR, Shida T, Schulz S, Aguiar M, Gygi SP, Bazan JF, Nachury MV,
JournalCell
PubMed ID20603001
The BBSome is a complex of Bardet-Biedl Syndrome (BBS) proteins that shares common structural elements with COPI, COPII, and clathrin coats. Here, we show that the BBSome constitutes a coat complex that sorts membrane proteins to primary cilia. The BBSome is the major effector of the Arf-like GTPase Arl6/BBS3, and ... More
RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins.
DNA double-strand breaks (DSBs) not only interrupt the genetic information, but also disrupt the chromatin structure, and both impairments require repair mechanisms to ensure genome integrity. We showed previously that RNF8-mediated chromatin ubiquitylation protects genome integrity by promoting the accumulation of repair factors at DSBs. Here, we provide evidence that, ... More
Calcium flickers steer cell migration.
AuthorsWei C, Wang X, Chen M, Ouyang K, Song LS, Cheng H,
JournalNature
PubMed ID19118385
Directional movement is a property common to all cell types during development and is critical to tissue remodelling and regeneration after damage. In migrating cells, calcium has a multifunctional role in directional sensing, cytoskeleton redistribution, traction force generation, and relocation of focal adhesions. Here we visualize high-calcium microdomains ('calcium flickers') ... More
FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination.
AuthorsDupont S, Mamidi A, Cordenonsi M, Montagner M, Zacchigna L, Adorno M, Martello G, Stinchfield MJ, Soligo S, Morsut L, Inui M, Moro S, Modena N, Argenton F, Newfeld SJ, Piccolo S,
JournalCell
PubMed ID19135894
The assembly of the Smad complex is critical for TGFbeta signaling, yet the mechanisms that inactivate or empower nuclear Smad complexes are less understood. By means of siRNA screen we identified FAM (USP9x), a deubiquitinase acting as essential and evolutionarily conserved component in TGFbeta and bone morphogenetic protein signaling. Smad4 ... More
Aberrant chromosome morphology in human cells defective for Holliday junction resolution.
AuthorsWechsler T, Newman S, West SC,
JournalNature
PubMed ID21399624
In somatic cells, Holliday junctions can be formed between sister chromatids during the recombinational repair of DNA breaks or after replication fork demise. A variety of processes act upon Holliday junctions to remove them from DNA, in events that are critical for proper chromosome segregation. In human cells, the BLM ... More
Imaging of Rab5 activity identifies essential regulators for phagosome maturation.
AuthorsKitano M, Nakaya M, Nakamura T, Nagata S, Matsuda M,
JournalNature
PubMed ID18385674
Efficient phagocytosis of apoptotic cells is crucial for tissue homeostasis and the immune response. Rab5 is known as a key regulator of the early endocytic pathway and we have recently shown that Rab5 is also implicated in apoptotic cell engulfment; however, the precise spatio-temporal dynamics of Rab5 activity remain unknown. ... More
From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus.
AuthorsMusunuru K, Strong A, Frank-Kamenetsky M, Lee NE, Ahfeldt T, Sachs KV, Li X, Li H, Kuperwasser N, Ruda VM, Pirruccello JP, Muchmore B, Prokunina-Olsson L, Hall JL, Schadt EE, Morales CR, Lund-Katz S, Phillips MC, Wong J, Cantley W, Racie T, Ejebe KG, Orho-Melander M, Melander O, Koteliansky V, Fitzgerald K, Krauss RM, Cowan CA, Kathiresan S, Rader DJ,
JournalNature
PubMed ID20686566
Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 strongly associated with both plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, ... More
A MicroRNA targeting dicer for metastasis control.
AuthorsMartello G, Rosato A, Ferrari F, Manfrin A, Cordenonsi M, Dupont S, Enzo E, Guzzardo V, Rondina M, Spruce T, Parenti AR, Daidone MG, Bicciato S, Piccolo S,
JournalCell
PubMed ID20603000
Although specific microRNAs (miRNAs) can be upregulated in cancer, global miRNA downregulation is a common trait of human malignancies. The mechanisms of this phenomenon and the advantages it affords remain poorly understood. Here we identify a microRNA family, miR-103/107, that attenuates miRNA biosynthesis by targeting Dicer, a key component of ... More
Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme.
AuthorsNakagawa K, Hirota Y, Sawada N, Yuge N, Watanabe M, Uchino Y, Okuda N, Shimomura Y, Suhara Y, Okano T,
JournalNature
PubMed ID20953171
Vitamin?K occurs in the natural world in several forms, including a plant form, phylloquinone (PK), and a bacterial form, menaquinones (MKs). In many species, including humans, PK is a minor constituent of hepatic vitamin?K content, with most hepatic vitamin?K content comprising long-chain MKs. Menaquinone-4 (MK-4) is ubiquitously present in extrahepatic ... More
Functional genomic screen for modulators of ciliogenesis and cilium length.
AuthorsKim J, Lee JE, Heynen-Genel S, Suyama E, Ono K, Lee K, Ideker T, Aza-Blanc P, Gleeson JG,
JournalNature
PubMed ID20393563
Primary cilia are evolutionarily conserved cellular organelles that organize diverse signalling pathways. Defects in the formation or function of primary cilia are associated with a spectrum of human diseases and developmental abnormalities. Genetic screens in model organisms have discovered core machineries of cilium assembly and maintenance. However, regulatory molecules that ... More
Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis.
AuthorsOberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P, Pop C, Hakem R, Salvesen GS, Green DR,
JournalNature
PubMed ID21368763
Caspase-8 has two opposing biological functions--it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development, T-lymphocyte activation, and resistance to necrosis induced by tumour necrosis factor-a (TNF-a) and related family ligands. Here we show that development ... More
Gp78 Cooperates with RMA1 in ER-associated Degradation of CFTR{Delta}F508.
AuthorsMorito D, Hirao K, Oda Y, Hosokawa N, Tokunaga F, Cyr DM, Tanaka K, Iwai K, Nagata K,
JournalMol Biol Cell
PubMed ID18216283
Monitoring Editor: Thomas Sommer Misfolded or improperly assembled proteins in the endoplasmic reticulum (ER) are exported into the cytosol and degraded via the ubiquitin-proteasome pathway, a process termed ER-associated degradation (ERAD). S. cerevisiae Hrd1p/Der3p is an ER membrane-spanning ubiquitin ligase that participates in ERAD of the cystic fibrosis transmembrane conductance ... More
RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins.
Accumulation of repair proteins on damaged chromosomes is required to restore genomic integrity. However, the mechanisms of protein retention at the most destructive chromosomal lesions, the DNA double-strand breaks (DSBs), are poorly understood. We show that RNF8, a RING-finger ubiquitin ligase, rapidly assembles at DSBs via interaction of its FHA ... More
Cohesin mediates transcriptional insulation by CCCTC-binding factor.
AuthorsWendt KS, Yoshida K, Itoh T, Bando M, Koch B, Schirghuber E, Tsutsumi S, Nagae G, Ishihara K, Mishiro T, Yahata K, Imamoto F, Aburatani H, Nakao M, Imamoto N, Maeshima K, Shirahige K, Peters JM,
JournalNature
PubMed ID18235444
Cohesin complexes mediate sister-chromatid cohesion in dividing cells but may also contribute to gene regulation in postmitotic cells. How cohesin regulates gene expression is not known. Here we describe cohesin-binding sites in the human genome and show that most of these are associated with the CCCTC-binding factor (CTCF), a zinc-finger ... More
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.
AuthorsIshikawa H, Ma Z, Barber GN,
JournalNature
PubMed ID19776740
The innate immune system is critical for the early detection of invading pathogens and for initiating cellular host defence countermeasures, which include the production of type I interferon (IFN). However, little is known about how the innate immune system is galvanized to respond to DNA-based microbes. Here we show that ... More
Force sensing by mechanical extension of the Src family kinase substrate p130Cas.
AuthorsSawada Y, Tamada M, Dubin-Thaler BJ, Cherniavskaya O, Sakai R, Tanaka S, Sheetz MP,
JournalCell
PubMed ID17129785
How physical force is sensed by cells and transduced into cellular signaling pathways is poorly understood. Previously, we showed that tyrosine phosphorylation of p130Cas (Cas) in a cytoskeletal complex is involved in force-dependent activation of the small GTPase Rap1. Here, we mechanically extended bacterially expressed Cas substrate domain protein (CasSD) ... More
Non-transcriptional control of DNA replication by c-Myc.
AuthorsDominguez-Sola D, Ying CY, Grandori C, Ruggiero L, Chen B, Li M, Galloway DA, Gu W, Gautier J, Dalla-Favera R,
JournalNature
PubMed ID17597761
The c-Myc proto-oncogene encodes a transcription factor that is essential for cell growth and proliferation and is broadly implicated in tumorigenesis. However, the biological functions required by c-Myc to induce oncogenesis remain elusive. Here we show that c-Myc has a direct role in the control of DNA replication. c-Myc interacts ... More
Microtubule plus-end-tracking proteins target gap junctions directly from the cell interior to adherens junctions.
AuthorsShaw RM, Fay AJ, Puthenveedu MA, von Zastrow M, Jan YN, Jan LY,
JournalCell
PubMed ID17289573
Gap junctions are intercellular channels that connect the cytoplasms of adjacent cells. For gap junctions to properly control organ formation and electrical synchronization in the heart and the brain, connexin-based hemichannels must be correctly targeted to cell-cell borders. While it is generally accepted that gap junctions form via lateral diffusion ... More
BRAG2/GEP100/IQSec1 Interacts with Clathrin and Regulates a5ß1 Integrin Endocytosis through Activation of ADP Ribosylation Factor 5 (Arf5).
AuthorsMoravec R, Conger KK, D'Souza R, Allison AB, Casanova JE,
JournalJ Biol Chem
PubMed ID22815487
ADP ribosylation factors (Arfs) are small GTP-binding proteins known for their role in vesicular transport, where they nucleate the assembly of coat protein complexes at sites of carrier vesicle formation. Similar to other GTPases, Arfs require guanine nucleotide exchange factors to catalyze GTP loading and activation. One subfamily of ArfGEFs, ... More
Low-density Lipoprotein Receptor-related Protein-1 (LRP1) Mediates Autophagy and Apoptosis Caused by Helicobacter pylori VacA.
AuthorsYahiro K, Satoh M, Nakano M, Hisatsune J, Isomoto H, Sap J, Suzuki H, Nomura F, Noda M, Moss J, Hirayama T,
JournalJ Biol Chem
PubMed ID22822085
In Helicobacter pylori infection, vacuolating cytotoxin (VacA)-induced mitochondrial damage leading to apoptosis is believed to be a major cause of cell death. It has also been proposed that VacA-induced autophagy serves as a host mechanism to limit toxin-induced cellular damage. Apoptosis and autophagy are two dynamic and opposing processes that ... More