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

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2014
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Confalonieri, Stefano
Bertalot, Giovanni
Di Fiore, Pier Paolo
Dietmaier, Wolfgang
Crespo, Piero
Macara, Ian G.
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Nature communications. 2014, 5, 4839. ISSN 0256-7865. eISSN 1303-6025. Available under: doi: 10.1038/ncomms5839
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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.

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570 Biowissenschaften, Biologie
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Biological sciences, Cell biology
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ISO 690BASCHIERI, Francesco, Stefano CONFALONIERI, Giovanni BERTALOT, Pier Paolo DI FIORE, Wolfgang DIETMAIER, Marcel LEIST, Piero CRESPO, Ian G. MACARA, Hesso FARHAN, 2014. Spatial control of Cdc42 signalling by a GM130-RasGRF complex regulates polarity and tumorigenesis. In: Nature communications. 2014, 5, 4839. ISSN 0256-7865. eISSN 1303-6025. Available under: doi: 10.1038/ncomms5839
BibTex
@article{Baschieri2014Spati-29329,
  year={2014},
  doi={10.1038/ncomms5839},
  title={Spatial control of Cdc42 signalling by a GM130-RasGRF complex regulates polarity and tumorigenesis},
  volume={5},
  issn={0256-7865},
  journal={Nature communications},
  author={Baschieri, Francesco and Confalonieri, Stefano and Bertalot, Giovanni and Di Fiore, Pier Paolo and Dietmaier, Wolfgang and Leist, Marcel and Crespo, Piero and Macara, Ian G. and Farhan, Hesso},
  note={Article Number: 4839}
}
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