title: Spatial control of Cdc42 signalling by a GM130-RasGRF complex regulates polarity and tumorigenesis.
abstract: The small GTPase Cdc42 is a key regulator of polarity, but little is known in mammals about its spatial regulation and the relevance of spatial Cdc42 pools for polarity. Here we report the identification of a GM130-RasGRF complex as a regulator of Cdc42 at the Golgi. Silencing GM130 results in RasGRF-dependent inhibition of the Golgi pool of Cdc42, but does not affect Cdc42 at the cell surface. Furthermore, active Cdc42 at the Golgi is important to sustain asymmetric front-rear Cdc42-GTP distribution in directionally migrating cells. Concurrent to Cdc42 inhibition, silencing GM130 also results in RasGRF-dependent Ras-ERK pathway activation. Moreover, depletion of GM130 is sufficient to induce E-cadherin downregulation, indicative of a loss in cell polarity and epithelial identity. Accordingly, GM130 expression is frequently lost in colorectal and breast cancer patients. These findings establish a previously unrecognized role for a GM130-RasGRF-Cdc42 connection in regulating polarity and tumorigenesis.
authors.affiliation: 1] University of Konstanz, 78464 Konstanz, Germany [2] Biotechnology Institute Thurgau, University of Konstanz, Kreuzlingen CH-8280, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Baschieri
authors.affiliation: 1] Molecular Medicine for Care Program, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy [2] IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Confalonieri
authors.affiliation: Molecular Medicine for Care Program, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bertalot
authors.affiliation: 1] Molecular Medicine for Care Program, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy [2] IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy [3] Dipartimento di Scienze della Salute, Università degli Studi di Milano, Via Antonio di Rudinì 8, 20142 Milan, Italy.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.affiliation: University of Regensburg, Institute of Pathology and molecular diagnostics, 93053 Regensbur, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dietmaier
authors.affiliation: University of Konstanz, 78464 Konstanz, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Leist
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Cantabria-SODERCAN. 39005 Santander, Spain.
authors.forename: Piero
authors.initials: P
authors.lastname: Crespo
authors.affiliation: Department of Cell &Developmental Biology, Vanderbilt University, Nashville, Tennessee 37235, USA.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Macara
authors.affiliation: 1] University of Konstanz, 78464 Konstanz, Germany [2] Biotechnology Institute Thurgau, University of Konstanz, Kreuzlingen CH-8280, Switzerland.
authors.forename: Hesso
authors.initials: H
authors.lastname: Farhan
mesh_terms: D015703:Antigens, CD; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism; D020663:ras Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D020666:ras-GRF1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D001324:Autoantigens; C513384:CDH1 protein, human; D015820:Cadherins; C097741:Golgin subfamily A member 2; D008565:Membrane Proteins; C513039:RASGRF1 protein, human; C504490:RASGRF2 protein, human; D064067:Rho Guanine Nucleotide Exchange Factors; D020663:ras Guanine Nucleotide Exchange Factors; D020666:ras-GRF1; D048052:Mitogen-Activated Protein Kinase 3; D020764:cdc42 GTP-Binding Protein