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Functional interaction between Smad3 and S100A4 (metastatin-1) for TGF-beta-mediated cancer cell invasiveness

Isao Matsuura1, Chen-Yu Lai, Keng-Nan Chiang

  • 1Division of Molecular and Genomic Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan. imatsuura@nhri.org.tw

The Biochemical Journal
|January 15, 2010
PubMed

Insights

S100A4 protein physically interacts with Smad3, enhancing transforming growth factor-beta (TGF-beta) signaling. This interaction promotes cancer cell metastasis and matrix metalloproteinase-9 expression, suggesting a co-operative role in malignant tumor progression.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Transforming growth factor-beta (TGF-beta) typically causes cytostasis in normal cells but promotes metastasis in cancer.
  • High TGF-beta expression correlates with poor prognosis in various cancers.
  • S100A4, a metastasis-associated protein, is implicated in cancer progression.

Purpose of the Study:

  • To investigate the interaction between S100A4 and Smad3, a key mediator of TGF-beta signaling.
  • To determine the functional consequences of this interaction on TGF-beta-induced gene expression and cell invasion.
  • To elucidate the role of S100A4 in TGF-beta-driven cancer metastasis.

Main Methods:

  • Co-immunoprecipitation assays to demonstrate physical interaction between S100A4 and Smad3.
  • Calcium-dependent binding assays.
  • Reporter gene assays to assess transcriptional activity.
  • Small interfering RNA (siRNA) mediated depletion of S100A4.
  • In vitro cell invasion assays.

Main Results:

  • S100A4 physically and functionally interacts with Smad3 in a calcium-dependent manner.
  • S100A4 potentiates the transcriptional activity of Smad3 and Smad2.
  • S100A4 enhances TGF-beta-induced matrix metalloproteinase-9 (MMP-9) expression and cell invasion.
  • Depletion of S100A4 attenuates TGF-beta-induced MMP-9 expression and invasion.

Conclusions:

  • S100A4 interacts with Smad3, enhancing TGF-beta signaling pathways.
  • S100A4 promotes cancer cell invasion and metastasis by potentiating TGF-beta effects.
  • S100A4 and TGF-beta may co-operatively drive metastatic activity in malignant tumors.

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