TGF-β-mediated activation of RhoA signalling is required for efficient V12HaRas and V600EBRAF transformation

Fleming, Y.M., Ferguson, G.J., Spender, L., Larsson, J., Karlsson, S., Ozanne, B.W., Grosse, R. and Inman, G.J. (2009) TGF-β-mediated activation of RhoA signalling is required for efficient V12HaRas and V600EBRAF transformation. Oncogene, 28(7), pp. 983-993. (doi: 10.1038/onc.2008.449) (PMID:19079344)

Abstract

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. broblasts, we show that oncogenic rewiring by transduction of (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 (V12)HaRas, V-Raf and (V600E)BRAF transformation and (V12)HaRas-mediated anchorage-independent growth. These findings identify a new pro-oncogenic activity of TGF-beta and indicate that tumours harbouring (V12)HaRas and (V600E)BRAF mutations may be susceptible to TGF-beta signalling inhibitors.

• Item Type: Articles
• Additional Information: This work was supported by an Association for International Cancer Research fellowship to GJI (GJI, YMF, GJF and LCS) and Cancer Research UK (YMF, GJI, GJF, LCS, and BWO).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Inman, Professor Gareth and Spender, Dr Lindsay and Fleming, Dr Yvonne and Ozanne, Professor Bradford
• Authors: Fleming, Y.M., Ferguson, G.J., Spender, L., Larsson, J., Karlsson, S., Ozanne, B.W., Grosse, R., and Inman, G.J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncogene
• Publisher: Springer Nature
• ISSN: 0950-9232
• ISSN (Online): 1476-5594