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Tiki proteins are substrates of membrane-type matrix metalloproteinases

Mingyi Li1, Jing Zheng1, Dong Luo1

  • 1Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.

FEBS Letters
|June 11, 2022
PubMed

Insights

Matrix metalloproteinase 15 (MMP15) degrades TIKI2, a Wnt-signaling inhibitor, on cell surfaces. This interaction releases Wnt signaling, revealing a novel regulatory mechanism for Tiki proteases.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • Tiki proteins are Wnt-specific proteases that inhibit Wnt signaling by cleaving Wnt proteins.
  • These glycosylphosphatidylinositol (GPI)-anchored proteases function in both Wnt-producing and Wnt-responsive cells.
  • The regulation of Tiki protein activity remains largely unknown.

Purpose of the Study:

  • To investigate the regulatory mechanisms governing Tiki protein function.
  • To identify proteases that interact with and modify Tiki proteins.
  • To understand how Tiki protein regulation impacts Wnt signaling.

Main Methods:

  • Co-immunoprecipitation assays to detect protein interactions.
  • Western blotting to assess protein degradation.
  • Cell-based assays to measure Wnt signaling activity.
  • Analysis of Tiki protein susceptibility to various matrix metalloproteinases (MMPs).

Main Results:

  • Matrix metalloproteinase 15 (MMP15) was found to interact with and degrade TIKI2 on the cell surface.
  • MMP15-mediated degradation of TIKI2 relieved the inhibitory effect of TIKI2 on Wnt signaling.
  • Tiki proteins were identified as substrates for MMP14, MMP15, and MMP16, but not MMP3 or MMP13.

Conclusions:

  • MMP15 plays a crucial role in regulating TIKI2 activity and Wnt signaling.
  • Matrix metalloproteinases (MMPs) represent a novel class of regulators for Tiki family proteases.
  • This study elucidates a new layer of control in Wnt signaling pathways through protease-mediated degradation.
Keywords:
MMP15MT-MMPTikiWnt

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