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Thiol isomerases negatively regulate the cellular shedding activity of ADAM17

Sofie H Willems1, Christopher J Tape, Peter L Stanley

  • 1Department of Oncology, Cambridge University, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge CB20RE, UK.

The Biochemical Journal
|March 30, 2010
PubMed

Insights

Thiol isomerases, like protein disulfide isomerase (PDI), maintain ADAM17 in an inactive state. Disrupting these isomerases activates ADAM17, revealing a new mechanism for cell signaling regulation.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Signaling

Background:

  • ADAM17 (a disintegrin and metalloproteinase) regulates cell-surface signaling by releasing soluble proligands.
  • The precise mechanisms controlling ADAM17 sheddase activity and activation remain unclear.
  • Redox environment and protein disulfide isomerase (PDI) roles in ADAM17 regulation are not fully understood.

Purpose of the Study:

  • To investigate the role of thiol isomerases in regulating ADAM17 activity.
  • To elucidate the mechanisms underlying ADAM17 activation through redox modulation.
  • To explore the potential involvement of disulfide bond isomerization in ADAM17 function.

Main Methods:

  • Development and utilization of a cell-based ADAM17 assay.
  • Investigating the impact of thiol isomerase down-regulation on ADAM17 activity.
  • Employing ELISA binding studies with novel fragment antibodies against ADAM17.
  • Analyzing the effects of altered redox environments (e.g., phorbol ester-induced reactive oxygen species) on ADAM17 activation.

Main Results:

  • Thiol isomerases, particularly PDI, were found to maintain ADAM17 in an inactive conformation.
  • Down-regulation of thiol isomerases significantly enhanced ADAM17 activation.
  • Changes in the redox environment, including mitochondrial reactive oxygen species modulation, influenced ADAM17 activity.
  • ELISA studies suggest that disulfide bond isomerization in ADAM17 leads to conformational changes that modulate its activity.

Conclusions:

  • Thiol isomerases play a crucial role in keeping ADAM17 inactive.
  • Redox-dependent regulation of ADAM17 activity is mediated by disulfide bond isomerization and conformational changes.
  • Further investigation into thiol isomerases is warranted for understanding the redox regulation of ADAM17.

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