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MT1-MMP recognition by ERM proteins and its implication in CD44 shedding

Shin-Ichi Terawaki1, Ken Kitano1, Miki Aoyama1

  • 1Structural Biology Laboratory, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara, 630-0192, Japan.

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
|August 21, 2015
PubMed

Insights

Membrane type 1-matrix metalloproteinase (MT1-MMP) binds radixin, an ezrin/radixin/moesin (ERM) protein, facilitating tumor cell invasion. This interaction, along with radixin binding CD44, anchors MT1-MMP to F-actin for substrate shedding.

Area of Science:

  • Molecular Cell Biology
  • Biochemistry
  • Cancer Research

Background:

  • Membrane type 1-matrix metalloproteinase (MT1-MMP) facilitates tumor invasion by shedding CD44.
  • Ezrin/radixin/moesin (ERM) proteins link cell surface proteins to the actin cytoskeleton.
  • CD44 shedding is crucial for tumor cell motility and invasion.

Purpose of the Study:

  • To elucidate the molecular mechanism by which MT1-MMP interacts with ERM proteins and CD44.
  • To investigate the role of radixin in recruiting MT1-MMP to CD44 for F-actin anchoring.
  • To understand how ERM proteins mediate the interaction between MT1-MMP and its substrate CD44.

Main Methods:

  • Co-immunoprecipitation assays to demonstrate protein interactions.
  • Crystal structure analysis of the MT1-MMP cytoplasmic tail bound to radixin's FERM domain.
  • Biochemical assays to confirm simultaneous binding of radixin to both MT1-MMP and CD44.

Main Results:

  • The cytoplasmic tail of MT1-MMP directly binds to the FERM domain of radixin.
  • Crystal structure reveals a unique binding interface between MT1-MMP and radixin subdomain A.
  • Radixin simultaneously binds MT1-MMP and CD44, mediating their colocalization and F-actin anchoring.

Conclusions:

  • ERM proteins, specifically radixin, act as crucial adaptors, linking MT1-MMP to CD44 and the F-actin cytoskeleton.
  • This ERM protein-mediated interaction facilitates MT1-MMP recruitment to CD44, accelerating substrate shedding.
  • The findings reveal a novel mechanism contributing to MT1-MMP-driven tumor cell invasion.

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