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Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

A G Remacle1, D V Rozanov, M Fugere

  • 1The Burnham Institute for Medical Research, La Jolla, CA 92037, USA.

Oncogene
|April 26, 2006
PubMed

Insights

Furin and related proprotein convertases (PCs) activate membrane type-1 matrix metalloproteinase (MT1-MMP), controlling its surface levels in cancer cells. This activation is crucial for pericellular proteolysis and cancer cell invasion.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Membrane type-1 matrix metalloproteinase (MT1-MMP) is an invasion-promoting enzyme crucial in cancer progression.
  • MT1-MMP requires proteolytic activation via prodomain cleavage to become functionally active.
  • Two potential furin cleavage sites exist within the MT1-MMP prodomain: R(89)-R-P-R-C(93) and R(108)-R-K-R-Y(112).

Purpose of the Study:

  • To investigate the role of furin and related proprotein convertases (PCs) in MT1-MMP activation and surface localization.
  • To determine which specific PCs cleave the identified motifs in MT1-MMP.
  • To explore the relationship between MT1-MMP activation state and its cellular uptake rate.

Main Methods:

  • Analysis of MT1-MMP prodomain sequences for furin cleavage motifs.
  • In vitro susceptibility assays using various PCs (furin, PC5/6, PC7, PACE4) against MT1-MMP peptide sequences.
  • Structural analysis of the MT1-MMP proenzyme to assess accessibility of cleavage sites.
  • Comparison of cellular uptake rates for latent MT1-MMP proenzyme versus active MT1-MMP.

Main Results:

  • The R(108)-R-K-R-Y(112) motif is cleaved by furin, PC5/6, PC7, and PACE4.
  • The R(89)-R-P-R-C(93) motif is susceptible to furin and PC5/6 but is structurally inaccessible in the proenzyme.
  • Furin and related PCs are essential for activating MT1-MMP and regulating its surface levels.
  • The uptake rate of the latent MT1-MMP proenzyme is significantly higher than that of the active enzyme.

Conclusions:

  • Furin and related PCs are key regulators of MT1-MMP activation and cell surface abundance.
  • The differential accessibility of cleavage sites influences MT1-MMP maturation and function.
  • The regulation of active MT1-MMP levels by PCs is critical for pericellular proteolysis and cancer cell invasion.

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