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 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 a GM130-RasGRF-Cdc42 connection in regulating polarity and tumorigenesis.

Spatial control of Cdc42 signalling by a GM130-RasGRF complex regulates polarity and tumorigenesis / Baschieri, F; Confalonieri, S; Bertalot, G; Di Fiore, Pp; Dietmaier, W; Leist, M; Crespo, P; Macara, Ig; Farhan, H. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 5:(2014), pp. 483901-483912. [10.1038/ncomms5839]

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

Bertalot G;
2014-01-01

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 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 a GM130-RasGRF-Cdc42 connection in regulating polarity and tumorigenesis.
2014
Baschieri, F; Confalonieri, S; Bertalot, G; Di Fiore, Pp; Dietmaier, W; Leist, M; Crespo, P; Macara, Ig; Farhan, H
Spatial control of Cdc42 signalling by a GM130-RasGRF complex regulates polarity and tumorigenesis / Baschieri, F; Confalonieri, S; Bertalot, G; Di Fiore, Pp; Dietmaier, W; Leist, M; Crespo, P; Macara, Ig; Farhan, H. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 5:(2014), pp. 483901-483912. [10.1038/ncomms5839]
File in questo prodotto:
File Dimensione Formato  
BASCHIERI.pdf

Solo gestori archivio

Tipologia: Versione editoriale (Publisher’s layout)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 1.91 MB
Formato Adobe PDF
1.91 MB Adobe PDF   Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/361184
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 73
  • ???jsp.display-item.citation.isi??? 68
social impact