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.