TGF-[beta]-mediated activation of RhoA signalling is required for efficient super(V12)HaRas and super(V600E)BRAF transformation
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...
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Published in | Oncogene Vol. 28; no. 7; pp. 983 - 993 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
01.02.2009
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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 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. |
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AbstractList | 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. |
Author | Larsson, J Ozanne, B W Karlsson, S Spender, L C Grosse, R Ferguson, G J Fleming, Y M Inman, G J |
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Title | TGF-[beta]-mediated activation of RhoA signalling is required for efficient super(V12)HaRas and super(V600E)BRAF transformation |
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