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

Y. M. Fleming, G. J. Ferguson, L. C. Spender, J. Larsson, S. Karlsson, B. W. Ozanne, R. Grosse, G. J. Inman (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    31 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)983-993
    Number of pages11
    JournalOncogene
    Volume28
    Issue number7
    DOIs
    Publication statusPublished - 19 Feb 2009

    Keywords

    • TGF-beta
    • RhoA
    • Ras
    • Raf
    • transformation
    • GROWTH-FACTOR-BETA
    • TRANSCRIPTION FACTORS
    • TUMOR-SUPPRESSOR
    • GTPASES
    • PATHWAYS
    • CANCER
    • RAS
    • REORGANIZATION
    • PROLIFERATION
    • KINASE

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