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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Online Access | Get full text |
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Summary: | 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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 23 ObjectType-Feature-2 |
ISSN: | 0950-9232 1476-5594 |
DOI: | 10.1038/onc.2008.449 |