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Membrane-Type 1 Matrix Metalloproteinase Downregulates Fibroblast Growth Factor-2 Binding to the Cell Surface and

Evelyne Tassone1, Cristina Valacca1, Paolo Mignatti1,2

  • 1Department of Cardiothoracic Surgery, New York University School of Medicine, New York.

Journal of Cellular Physiology
|July 3, 2014
PubMed

Insights

Membrane-type 1 matrix metalloproteinase (MT1-MMP) degrades fibroblast growth factor-2 (FGF-2) on tumor cell surfaces. This proteolytic action reduces FGF-2 signaling, impacting cell migration and invasion.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14) is a transmembrane proteinase involved in extracellular matrix degradation and cell function regulation.
  • Fibroblast growth factor-2 (FGF-2) signaling plays a crucial role in various cellular processes, including tumor growth and metastasis.

Purpose of the Study:

  • To investigate the mechanism by which MT1-MMP influences FGF-2 signaling in tumor cells.
  • To determine the role of MT1-MMP's proteolytic activity in regulating FGF-2 binding and downstream signaling.

Main Methods:

  • Assessing FGF-2 binding to cell surfaces in MT1-MMP expressing and non-expressing tumor cells.
  • Analyzing ERK1/2 MAP kinase activation in response to FGF-2 stimulation.
  • Evaluating the impact of MT1-MMP mutations (proteolytically inactive, hemopexin-like domain-deleted, cytoplasmic domain-deleted) on FGF-2 signaling.
  • Measuring FGFR-1 and -4 expression levels.
  • Quantifying cell surface-associated FGF-2 at low and high affinity binding sites.
  • Assessing FGF-2-induced tumor cell migration and invasion in vitro.

Main Results:

  • MT1-MMP expression downregulates FGF-2 signaling by reducing cell surface-bound FGF-2, particularly at low-affinity sites.
  • Proteolytic activity of MT1-MMP is essential for the downregulation of FGF-2 signaling, as inactive mutants do not exhibit this effect.
  • MT1-MMP expression leads to decreased activation of ERK1/2 MAP kinase upon FGF-2 stimulation.
  • Downregulation of FGFR-1 and -4 expression was observed in MT1-MMP expressing cells.
  • MT1-MMP significantly reduces tumor cell migration and invasion induced by FGF-2.

Conclusions:

  • MT1-MMP exerts proteolytic control over FGF-2 signaling by diminishing FGF-2 binding to low-affinity sites on the cell surface.
  • This downregulation of FGF-2 binding ultimately leads to decreased cellular responses, including reduced migration and invasion.
  • MT1-MMP's proteolytic activity is a key mechanism for modulating FGF-2-driven biological processes in tumor cells.

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