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A disintegrin and metalloenzyme (ADAM) 17 activation is regulated by α5β1 integrin in kidney mesangial cells

Pal Gooz1, Yujing Dang, Shigeki Higashiyama

  • 1Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.

Plos One
|March 14, 2012
PubMed
Abstract

Insights

Beta-1 integrin regulates ADAM17 activity, impacting kidney disease progression. Targeting this interaction may offer new therapeutic strategies for chronic kidney diseases by controlling ADAM17 enzyme function.

Area of Science:

  • Cell Biology
  • Integrin Signaling
  • Enzyme Regulation

Background:

  • ADAM17 (a disintegrin and metalloenzyme) is implicated in inflammatory and proliferative kidney diseases.
  • Understanding ADAM17 regulation is crucial for treating chronic kidney diseases like fibrosis and polycystic kidney disease.
  • The role of α5β1 integrin in ADAM17 regulation during G protein-coupled receptor (GPCR) stimulation is largely unknown.

Purpose of the Study:

  • To characterize the role of α5β1 integrin in regulating ADAM17 activity.
  • To investigate the interaction between α5β1 integrin and ADAM17 during GPCR stimulation.
  • To explore the therapeutic potential of targeting the α5β1 integrin-ADAM17 interaction in kidney diseases.

Main Methods:

  • Co-immunoprecipitation to detect ADAM17/α5β1 integrin interaction in mesangial cell lysates.
  • Fluorescence immunostaining and proximity ligation assays to determine interaction localization.
  • Cell-free assays with purified proteins to assess binding and inhibition.
  • Enzyme activity assays using HB-EGF shedding and β1 integrin modulation (overexpression/siRNA).

Main Results:

  • α5β1 integrin co-precipitated with ADAM17 in unstimulated cells, dissociating upon 5-HT stimulation.
  • ADAM17 and α5β1 integrin interaction occurs in the perinuclear region.
  • Purified α5β1 integrin inhibited ADAM17 activity in a dose-dependent manner, influenced by integrin conformation.
  • Overexpression of β1 integrin blocked 5-HT-induced HB-EGF shedding, while silencing β1 integrin enhanced ADAM17 activity.

Conclusions:

  • β1 integrin plays a significant physiological role in regulating ADAM17 activity.
  • The α5β1 integrin-ADAM17 interaction is a key regulatory mechanism.
  • Targeting the binding between α5β1 integrin and ADAM17 presents a potential therapeutic strategy for chronic kidney diseases.

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