Probing the transcriptional consequences of Ras and Rho activation
1Cancer Research UK London Research Institute, London, UK,2Francis Crick Institute, London, UK
Signalling by small GTPases of the Ras and Rho families controls proliferation, adhesion and invasion of both normal and transformed cells. We study how signalling from these regulators interfaces with transcriptional programmes. An initial focus on the response to acute mitogenic signals such as serum and growth factors led to the discovery of the transcriptional regulator SRF, which works in partnership with two families of signal-regulated cofactors: the TCFs, which are regulated by Ras-MAP Kinase signalling, and the MRTFs, which respond to Rho GTPase-mediated alterations in cytoskeletal dynamics. The MRTFs share a novel G-actin binding element, the RPEL motif, with other protein families involved in cytoskeletal control, and represent a new paradigm for signal transduction, in which G-actin acts as a signalling molecule. Recent studies of two aspects of this system will be discussed. The first area concerns to what extent the SRF network, and particularly TCF-SRF signalling, directs the initial transcription response to MAP kinase activation, and how this system can be used to establish a functional hierarchy between transcription factor activity, chromatin modifications and transcription. The second area concerns molecular mechanisms and transcriptional targets for the MRTF-SRF pathway. Genomic studies indicate that MRTF-SRF signalling controls the transcription of scores of genes involved in invasion, metastasis and mechanosensing.