Spatial control of Cdc42 signalling by a GM130-RasGRF complex regulates polarity and tumorigenesis

Autor: Giovanni Bertalot, Hesso Farhan, Marcel Leist, Pier Paolo Di Fiore, Piero Crespo, Francesco Baschieri, Wolfgang Dietmaier, Stefano Confalonieri, Ian G. Macara
Přispěvatelé: Universidad de Cantabria, Ministero dell'Istruzione, dell'Università e della Ricerca, Associazione Italiana per la Ricerca sul Cancro, Fondazione Antonio Carlo Monzino, Université de Bordeaux, Ministero della Salute, University of Konstanz, Biotechnology Institute Thurgau, German Research Foundation, European Research Council, European Commission, Company of Biologists
Rok vydání: 2014
Předmět:
Polarity (physics)
Carcinogenesis
MAP Kinase Signaling System
Regulator
General Physics and Astronomy
CDC42
macromolecular substances
Biology
Autoantigens
General Biochemistry
Genetics and Molecular Biology
Article
symbols.namesake
Ras-GRF1
Antigens
CD
Cell Line
Tumor
ddc:570
Cell polarity
Humans
Small GTPase
Gene Silencing
cdc42 GTP-Binding Protein
Multidisciplinary
Mitogen-Activated Protein Kinase 3
ras-GRF1
Cell Polarity
Membrane Proteins
General Chemistry
Golgi apparatus
16. Peace & justice
Cadherins
Biological sciences
Cell biology
3. Good health
Cell biology
Gene Expression Regulation
Neoplastic
Cdc42 GTP-Binding Protein
symbols
MCF-7 Cells
ras Guanine Nucleotide Exchange Factors
biological phenomena
cell phenomena
and immunity
Rho Guanine Nucleotide Exchange Factors
Signal Transduction
Zdroj: Nature Communications. 2014 Sep 11;5:4839
UCrea Repositorio Abierto de la Universidad de Cantabria
Universidad de Cantabria (UC)
Digital.CSIC. Repositorio Institucional del CSIC
instname
Popis: PMCID: PMC4449154.-- et al.
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. Concurrently to Cdc42 inhibition, silencing GM130 also results in RasGRF-dependent Ras-ERK pathway activation. Moreover, depletion of GM130 is sufficient to induce E-cadherin down-regulation, 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 the GM130-RasGRF-Cdc42 connection in regulating polarity and tumourigenesis.
HF is supported by the German Science Foundation (DFG), by the Biotechnology Institute Thurgau, and by the Young Scholar Fund of the University of Konstanz. FB acknowledges support by a fellowship from the Company of Biologists. We thank Beate Reiler for excellent technical assistance on staining the tissue samples. We thank Elisabeth Genot and Paolo Ciufici (University of Bordeaux) for help with the GTP-Cdc42 staining. PPDF acknowledges support by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC IG 14404), MIUR (the Italian Ministry of University and Scientific Research), the Italian Ministry of Health, the European Research Council (Mammastem Project) and The Monzino Foundation.
Databáze: OpenAIRE
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