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The tetraspanin network modulates MT1-MMP cell surface trafficking

H M Schröder1, S C Hoffmann, M Hecker

  • 1Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, Heidelberg University, 69120 Heidelberg, Germany. h.schroeder@physiologie.uni-heidelberg.de

The International Journal of Biochemistry & Cell Biology
|March 19, 2013
PubMed

Insights

Tetraspanins regulate the cell surface expression and function of membrane-type 1 matrix metalloproteinase (MT1-MMP). These interactions, occurring in the endoplasmic reticulum, control MT1-MMP

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Membrane-type 1 matrix metalloproteinase (MT1-MMP) is crucial for physiological and pathophysiological processes, including extracellular matrix degradation and MMP-2 activation.
  • Cell surface expression and trafficking of MT1-MMP are key regulators of its proteolytic activity.
  • Tetraspanins are membrane proteins known to organize membrane microdomains and regulate the trafficking of associated proteins.

Purpose of the Study:

  • To investigate the interaction between MT1-MMP and tetraspanins.
  • To determine the effects of tetraspanin association on MT1-MMP intracellular trafficking.
  • To elucidate the impact of tetraspanin binding on MT1-MMP proteolytic function.

Main Methods:

  • Yeast two-hybrid screening to identify interacting proteins.
  • Immunoprecipitation to confirm MT1-MMP interactions with tetraspanins and MAL.
  • Analysis of MT1-MMP truncation constructs and mutants to map interaction domains.
  • Subcellular localization studies using models of post-translational processing.
  • Functional assays measuring pro-MMP-2 activation and collagen invasion.

Main Results:

  • MT1-MMP interacts with EWI-2, and stably associates with tetraspanins (CD9, CD37, CD53, CD63, CD81, CD82) and MAL.
  • The hemopexin domain of MT1-MMP mediates interaction with tetraspanins and MAL.
  • Interactions occur in the endoplasmic reticulum and are independent of MT1-MMP O-glycosylation.
  • Tetraspanins differentially modulate MT1-MMP cell surface localization, pro-MMP-2 activation, and collagen invasion capacity.
  • The extent of tetraspanin-MT1-MMP association did not correlate with functional impact.

Conclusions:

  • Tetraspanins and MAL bind to the hemopexin domain of MT1-MMP during its endoplasmic reticulum processing.
  • Tetraspanins distinctly regulate MT1-MMP subcellular localization and proteolytic functions.
  • Tetraspanin networks offer a mechanism to control MT1-MMP activity at the cell surface.

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