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TGF-beta and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print Cited Medium: Print ISSN: 0950-9232 (Print) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE
    • Publication Information:
      Publication: <2002->: Basingstoke : Nature Publishing Group
      Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-
    • Subject Terms:
      JNK Mitogen-Activated Protein Kinases*; DNA-Binding Proteins/*metabolism ; Hepatocyte Growth Factor/*pharmacology ; Mitogen-Activated Protein Kinase Kinases/*metabolism ; Signal Transduction/*physiology ; Trans-Activators/*metabolism ; Transforming Growth Factor beta/*pharmacology; Animals ; Cell Line ; Genetic Vectors ; MAP Kinase Kinase 4 ; MAP Kinase Signaling System/drug effects ; MAP Kinase Signaling System/physiology ; Phosphorylation ; Rats ; Recombinant Proteins/metabolism ; Signal Transduction/drug effects ; Smad2 Protein ; Smad3 Protein ; Stomach
    • Abstract:
      Although hepatocyte growth factor (HGF) can act synergistically or antagonistically with transforming growth factor-beta (TGF-beta) signaling, molecular mechanism of their crosstalk remains unknown. Using antibodies which selectively distinguished receptor-regulated Smads (R-Smads) phosphorylated at linker regions from those at C-terminal regions, we herein showed that either HGF or TGF-beta treatment of normal stomach-origin cells activated the JNK pathway, thereafter inducing endogenous R-Smads phosphorylation at linker regions. However, the phosphorylation at their C-terminal regions was not induced by HGF treatment. The activated JNK could directly phosphorylate R-Smads in vitro at the same sites that were phosphorylated in response to TGF-beta or HGF in vivo. Thus, the linker regions of R-Smads were the common phosphorylation sites for HGF and TGF-beta signaling pathways. The phosphorylation induced by simultaneous treatment with HGF and TGF-beta allowed R-Smads to associate with Smad4 and to translocate into the nucleus. JNK pathway involved HGF and TGF-beta-mediated infiltration potency since a JNK inhibitor SP600125 caused the reduction of invasive capacity induced by HGF and TGF-beta signals. Moreover, a combined treatment with HGF and TGF-beta led to a potent increase in plasminogen activator inhibitor type 1 transcriptional activity through Smad3 phosphorylation at the linker region. In contrast, HGF treatment reduced TGF-beta-dependent activation of p15INK4B promoter, in which Smad3 phosphorylation at the C-terminal region was involved. In conclusion, HGF and TGF-beta transmit the signals through JNK-mediated R-Smads phosphorylation at linker regions.
    • Accession Number:
      0 (DNA-Binding Proteins)
      0 (Recombinant Proteins)
      0 (Smad2 Protein)
      0 (Smad2 protein, rat)
      0 (Smad3 Protein)
      0 (Smad3 protein, rat)
      0 (Trans-Activators)
      0 (Transforming Growth Factor beta)
      67256-21-7 (Hepatocyte Growth Factor)
      EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
      EC 2.7.12.2 (MAP Kinase Kinase 4)
      EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
    • Publication Date:
      Date Created: 20040825 Date Completed: 20041102 Latest Revision: 20220227
    • Publication Date:
      20231215
    • Accession Number:
      10.1038/sj.onc.1207981
    • Accession Number:
      15326485