TGF-[beta]-mediated activation of RhoA signalling is required for efficient super(V12)HaRas and super(V600E)BRAF transformation

• Published in: Oncogene Vol. 28; no. 7; pp. 983 - 993
• Main Authors: Fleming, Y M, Ferguson, G J, Spender, L C, Larsson, J, Karlsson, S, Ozanne, B W, Grosse, R, Inman, G J
• Format: Journal Article
• Language: English
• Published: 01.02.2009
• DOI: 10.1038/onc.2008.449
• ISSN: 0950-9232

Transforming growth factor [beta]-1 (TGF-[beta]) acts as both a tumour suppressor and a tumour promoter in a context-dependent manner. The tumour- promoting activities of TGF-[beta] are likely to result from a combination of Smad and non-Smad signalling pathways but remain poorly understood. Here we show that TGF-[beta]-mediated activation of RhoA is dependent on the kinase activity of ALK5 and that continuous ALK5 activity maintains basal RhoA-ROCK signalling, cell morphology and actin dynamics in serum-starved rodent fibroblasts independently of Smad2, Smad3 and Smad4. In immortalized human diploid fibroblasts, we show that oncogenic rewiring by transduction of super(V12)HaRas instigates regulation of RhoA-ROCK signalling through an autocrine TGF-[beta]1-ALK5 pathway. Furthermore, we show that ALK5-mediated activation of RhoA is required for efficient super(V12)HaRas, V-Raf and super(V600E)BRAF transformation and super(V12)HaRas-mediated anchorage-independent growth. These findings identify a new pro-oncogenic activity of TGF-[beta] and indicate that tumours harbouring super(V12)HaRas and super(V600E)BRAF mutations may be susceptible to TGF-[beta] signalling inhibitors.