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TIMP-2 Interaction with MT1-MMP Activates the AKT Pathway and Protects Tumor Cells from Apoptosis

Cristina Valacca1, Evelyne Tassone1, Paolo Mignatti2

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

Plos One
|September 3, 2015
PubMed

Insights

Tissue inhibitor of metalloproteinases-2 (TIMP-2) binding to membrane-type 1 matrix metalloproteinase (MT1-MMP) activates AKT and ERK1/2 pathways. This interaction influences tumor cell apoptosis based on the extracellular environment and stimulus.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a transmembrane proteinase involved in extracellular matrix degradation and intracellular signaling.
  • Previous studies demonstrated that tissue inhibitor of metalloproteinases-2 (TIMP-2) binding to MT1-MMP activates the Ras-ERK1/2 pathway, influencing cell proliferation, migration, and tumor growth.
  • The precise mechanisms by which MT1-MMP and TIMP-2 interaction modulates intracellular signaling and cell fate remain incompletely understood.

Purpose of the Study:

  • To investigate the role of TIMP-2 binding to MT1-MMP in activating AKT signaling.
  • To elucidate the mechanisms underlying TIMP-2-mediated activation of AKT and ERK1/2 pathways.
  • To determine how TIMP-2/MT1-MMP interactions affect tumor cell apoptosis in response to different stimuli and extracellular environments.

Main Methods:

  • Cell culture experiments using MT1-MMP expressing cells.
  • Western blotting to assess the activation of signaling pathways (ERK1/2, AKT).
  • Analysis of apoptosis induction under various conditions (serum starvation, 3D collagen).
  • Investigating the role of Fibroblast growth factor receptor-1 (FGFR1) and Ras in signal transduction.

Main Results:

  • TIMP-2 binding to MT1-MMP induces rapid and sustained AKT activation, independent of MT1-MMP's proteolytic activity.
  • Fibroblast growth factor receptor-1 mediates TIMP-2 induction of ERK1/2 but not AKT activation.
  • Ras activation is crucial for transducing TIMP-2-mediated signals to both ERK1/2 and AKT pathways.
  • TIMP-2/MT1-MMP interaction protects tumor cells from serum starvation-induced apoptosis but promotes apoptosis induced by 3D type I collagen in epithelial cancer cells.

Conclusions:

  • TIMP-2 binding to MT1-MMP activates both AKT and ERK1/2 signaling pathways through a Ras-dependent mechanism.
  • The proteolytic activity of MT1-MMP is not required for TIMP-2-induced AKT activation.
  • The functional outcome of TIMP-2/MT1-MMP interaction on tumor cell apoptosis is context-dependent, offering either pro- or anti-apoptotic signaling based on the extracellular milieu and specific apoptotic trigger.

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