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Shedding of kidney injury molecule-1 by membrane-type 1 matrix metalloproteinase

Luyang Guo1, Takahisa Takino, Yoshio Endo

  • 1Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.

Journal of Biochemistry
|July 31, 2012
PubMed

Insights

Membrane-type 1 matrix metalloproteinase (MT1-MMP) cleaves kidney injury molecule-1 (KIM-1), reducing its cell-surface levels. This cleavage by MT1-MMP abrogates KIM-1

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • Kidney injury molecule-1 (KIM-1) is a transmembrane protein implicated in renal injury and cellular processes.
  • Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a key enzyme involved in extracellular matrix remodeling and cell invasion.

Purpose of the Study:

  • To investigate the interaction between KIM-1 and MT1-MMP.
  • To determine the functional consequences of KIM-1 cleavage by MT1-MMP on cellular behavior.

Main Methods:

  • Co-expression of KIM-1 and MT1-MMP in HEK293T cells.
  • Site-directed mutagenesis of KIM-1 to identify the cleavage site.
  • Stable transfection of HT1080 cells with KIM-1 and its mutants.
  • Treatment with MMP inhibitor (BB-94) and MT1-MMP siRNA.
  • Assessment of cellular functions including phagocytosis, adhesion, spreading, invasion, migration, and metastasis.

Main Results:

  • MT1-MMP cleaves the KIM-1 ectodomain at the juxtamembrane region.
  • MT1-MMP mediates the shedding of KIM-1 from the cell surface.
  • High KIM-1 expression enhances bacterial phagocytosis but reduces cell adhesion and spreading on collagen.
  • KIM-1 negatively regulates cellular functions involving collagen interaction, including invasion, migration, and metastasis.
  • MT1-MMP abrogates these KIM-1-mediated regulatory functions via cleavage and shedding.

Conclusions:

  • KIM-1 negatively regulates cellular functions, particularly those involving collagen interactions.
  • MT1-MMP plays a critical role in modulating KIM-1 function by cleaving and shedding its ectodomain.
  • The MT1-MMP-mediated cleavage of KIM-1 releases it from the cell surface, thereby abrogating its inhibitory effects on cellular functions.

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