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Published on: March 5, 2018

Cdc42 is a substrate for caspases and influences Fas-induced apoptosis

S Tu1, R A Cerione

  • 1Department of Molecular Medicine, Veterinary Medical Center, Baker Laboratory, Cornell University, Ithaca, New York, 14853, USA.

The Journal of Biological Chemistry
|March 30, 2001
PubMed

Insights

The Ras-related GTP-binding protein Cdc42 is cleaved by caspases during Fas-mediated apoptosis. This degradation allows for a maximal apoptotic response, highlighting Cdc42

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Apoptosis Research

Background:

  • Fas-mediated apoptosis involves caspase activation and substrate cleavage.
  • Cellular viability depends on intact substrates.
  • Ras-related GTP-binding proteins play roles in cellular processes.

Purpose of the Study:

  • To investigate the susceptibility of Cdc42 to caspase-mediated proteolysis.
  • To determine the role of Cdc42 cleavage in Fas-induced apoptosis.
  • To identify the molecular mechanisms underlying Cdc42 degradation.

Main Methods:

  • Incubation of various cell lines (NIH3T3, T47D, COS-7) with Fas ligand.
  • Analysis of Cdc42 protein levels and cleavage products using Western blotting.
  • Site-directed mutagenesis to identify critical cleavage sequences.
  • Assays to measure apoptosis induction and protection.

Main Results:

  • Cdc42 is specifically cleaved by caspase-3 and caspase-7, but not caspase-6 or caspase-8.
  • A consensus DXXD sequence upstream of the Rho insert region mediates caspase sensitivity.
  • Mutations or removal of the cleavage site render Cdc42 resistant to degradation and protect cells from apoptosis.
  • Rac, but not Rho or Ras, is also a caspase substrate.

Conclusions:

  • Cdc42 acts downstream of Fas signaling and its caspase-mediated degradation is crucial for maximal apoptotic response.
  • The cleavage of Cdc42 by caspases is a specific event regulated by a DXXD motif.
  • Targeting Cdc42 cleavage may offer a therapeutic strategy for modulating apoptosis.

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