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 (V12)HaRas instigates regulation of RhoA-ROCK signalling through an autocrine TGF-beta1-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / metabolism
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Animals
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Benzamides / pharmacology
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Blotting, Western
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Cells, Cultured
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Cytoskeleton
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Dioxoles / pharmacology
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Enzyme-Linked Immunosorbent Assay
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Fluorescent Antibody Technique
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Genes, ras / physiology*
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Guanosine Triphosphate / metabolism
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Humans
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Mice
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NIH 3T3 Cells
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins B-raf / genetics*
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Proto-Oncogene Proteins B-raf / metabolism
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Rats
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction*
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Smad3 Protein / metabolism
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Smad4 Protein / metabolism
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Transfection
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Transforming Growth Factor beta / pharmacology*
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rho-Associated Kinases / metabolism
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rhoA GTP-Binding Protein / genetics*
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rhoA GTP-Binding Protein / metabolism
Substances
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4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
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Actins
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Benzamides
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Dioxoles
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Receptors, Transforming Growth Factor beta
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Smad3 Protein
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Smad4 Protein
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Transforming Growth Factor beta
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Guanosine Triphosphate
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins B-raf
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rho-Associated Kinases
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Receptor, Transforming Growth Factor-beta Type I
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TGFBR1 protein, human
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Tgfbr1 protein, mouse
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Tgfbr1 protein, rat
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rhoA GTP-Binding Protein