RasGRF suppresses Cdc42-mediated tumour cell movement, cytoskeletal dynamics and transformation

Abstract

Individual tumour cells move in three-dimensional environments with either a rounded or an elongated ‘mesenchymal’ morphology. These two modes of movement are tightly regulated by Rho family GTPases: elongated movement requires activation of Rac1, whereas rounded/amoeboid movement engages specific Cdc42 and Rho signalling pathways. In siRNA screens targeting the genes encoding guanine nucleotide exchange factors (GEFs), we found that the Ras GEF RasGRF2 regulates conversion between elongated- and rounded-type movement. RasGRF2 suppresses rounded movement by inhibiting the activation of Cdc42 independently of its capacity to activate Ras. RasGRF2 and RasGRF1 directly bind to Cdc42, outcompeting Cdc42 GEFs, thereby preventing Cdc42 activation. By this mechanism, RasGRFs regulate other Cdc42-mediated cellular processes such as the formation of actin spikes, transformation and invasion in vitro and in vivo. These results demonstrate a role for RasGRF GEFs as negative regulators of Cdc42 activation. The Ras GEF Ras-GRF2 is found to inhibit the activity of the Cdc42 Rho GTPase independently of its Ras-activating function. Binding of Ras-GRF2 to Cdc42 prevents its activation by Cdc42 GEFs suppressing Cdc42-mediated cell migration, invasion and transformation.

Cite this article

Calvo, F., Sanz-Moreno, V., Agudo-Ibáñez, L. et al. RasGRF suppresses Cdc42-mediated tumour cell movement, cytoskeletal dynamics and transformation. Nat Cell Biol 13, 819–826 (2011). https://doi.org/10.1038/ncb2271

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