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

Francesco Baschieri, Stefano Confalonieri, Giovanni Bertalot, Pier Paolo Di Fiore, Wolfgang Dietmaier, Marcel Leist, Piero Crespo, Ian G. Macara and Hesso Farhan ()
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Francesco Baschieri: University of Konstanz
Stefano Confalonieri: Molecular Medicine for Care Program, European Institute of Oncology
Giovanni Bertalot: Molecular Medicine for Care Program, European Institute of Oncology
Pier Paolo Di Fiore: Molecular Medicine for Care Program, European Institute of Oncology
Wolfgang Dietmaier: University of Regensburg, Institute of Pathology and molecular diagnostics
Marcel Leist: University of Konstanz
Piero Crespo: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)—Universidad de Cantabria—SODERCAN
Ian G. Macara: Vanderbilt University
Hesso Farhan: University of Konstanz

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5839

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