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

    29 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

    Cite this

    Fleming, Y. M. ; Ferguson, G. J. ; Spender, L. C. ; Larsson, J. ; Karlsson, S. ; Ozanne, B. W. ; Grosse, R. ; Inman, G. J. / TGF-beta-mediated activation of RhoA signalling is required for efficient (V12)HaRas and (V600E)BRAF transformation. In: Oncogene. 2009 ; Vol. 28, No. 7. pp. 983-993.
    @article{85a205a1ca794441880736fecbe5f439,
    title = "TGF-beta-mediated activation of RhoA signalling is required for efficient (V12)HaRas and (V600E)BRAF transformation",
    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.",
    keywords = "TGF-beta, RhoA, Ras, Raf, transformation, GROWTH-FACTOR-BETA, TRANSCRIPTION FACTORS, TUMOR-SUPPRESSOR, GTPASES, PATHWAYS, CANCER, RAS, REORGANIZATION, PROLIFERATION, KINASE",
    author = "Fleming, {Y. M.} and Ferguson, {G. J.} and Spender, {L. C.} and J. Larsson and S. Karlsson and Ozanne, {B. W.} and R. Grosse and Inman, {G. J.}",
    year = "2009",
    month = "2",
    day = "19",
    doi = "10.1038/onc.2008.449",
    language = "English",
    volume = "28",
    pages = "983--993",
    journal = "Oncogene",
    issn = "0950-9232",
    publisher = "Nature Publishing Group",
    number = "7",

    }

    TGF-beta-mediated activation of RhoA signalling is required for efficient (V12)HaRas and (V600E)BRAF transformation. / Fleming, Y. M.; Ferguson, G. J.; Spender, L. C.; Larsson, J.; Karlsson, S.; Ozanne, B. W.; Grosse, R.; Inman, G. J. (Lead / Corresponding author).

    In: Oncogene, Vol. 28, No. 7, 19.02.2009, p. 983-993.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - TGF-beta-mediated activation of RhoA signalling is required for efficient (V12)HaRas and (V600E)BRAF transformation

    AU - Fleming, Y. M.

    AU - Ferguson, G. J.

    AU - Spender, L. C.

    AU - Larsson, J.

    AU - Karlsson, S.

    AU - Ozanne, B. W.

    AU - Grosse, R.

    AU - Inman, G. J.

    PY - 2009/2/19

    Y1 - 2009/2/19

    N2 - 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.

    AB - 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.

    KW - TGF-beta

    KW - RhoA

    KW - Ras

    KW - Raf

    KW - transformation

    KW - GROWTH-FACTOR-BETA

    KW - TRANSCRIPTION FACTORS

    KW - TUMOR-SUPPRESSOR

    KW - GTPASES

    KW - PATHWAYS

    KW - CANCER

    KW - RAS

    KW - REORGANIZATION

    KW - PROLIFERATION

    KW - KINASE

    UR - http://www.scopus.com/inward/record.url?scp=60549095395&partnerID=8YFLogxK

    U2 - 10.1038/onc.2008.449

    DO - 10.1038/onc.2008.449

    M3 - Article

    VL - 28

    SP - 983

    EP - 993

    JO - Oncogene

    JF - Oncogene

    SN - 0950-9232

    IS - 7

    ER -