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

Abstract

Fas-mediated apoptosis results in the activation of caspases, which subsequently cleave cellular substrates that are essential for normal cell viability. In the present study, we show that the Ras-related GTP-binding protein Cdc42 is susceptible to caspase-catalyzed proteolysis in a number of cell lines, including NIH3T3 fibroblasts, human breast cancer cells (e.g. T47D), and COS-7 cells. Both caspase-3 and caspase-7 were able to catalyze the cleavage of Cdc42, whereas caspase-6 and caspase-8 were without effect. The susceptibility to the caspase-stimulated degradation is specific; although Rac can also serve as a caspase substrate, neither Rho nor Ras is degraded. Caspase sensitivity is conferred by a consensus sequence (DXXD) that lies immediately upstream of the Rho insert regions (residues 122-134) of Cdc42 and Rac. The removal of a stretch of residues (120) that includes the insert region or site-directed mutagenesis of either aspartic acid 118 or 121 within a constitutively active background (i.e. Cdc42(F28L)) as well as a wild-type Cdc42 background yields Cdc42 molecules that provide a marked protection against Fas ligand-induced apoptosis. Overall, these results are consistent with a model in which Cdc42 acts downstream of Fas, perhaps to influence the rate of apoptosis, with the ultimate caspase-mediated degradation of Cdc42 then allowing for a maximal apoptotic response.

• Authors: S Tu, R A Cerione
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 276 Issue 22 Pg. 19656-63 (Jun 01 2001) ISSN: 0021-9258 [Print] United States
• PMID: 11278572 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• FASLG protein, human
• Fas Ligand Protein
• Fasl protein, mouse
• Membrane Glycoproteins
• Recombinant Proteins
• fas Receptor
• Aspartic Acid
• CASP6 protein, human
• CASP8 protein, human
• CASP9 protein, human
• Casp6 protein, mouse
• Casp8 protein, mouse
• Casp9 protein, mouse
• Caspase 6
• Caspase 8
• Caspase 9
• Caspases
• cdc42 GTP-Binding Protein

Topics

• 3T3 Cells
• Animals
• Apoptosis
• Aspartic Acid (metabolism)
• COS Cells
• Caspase 6
• Caspase 8
• Caspase 9
• Caspases (chemistry, metabolism)
• Cell Survival
• Dose-Response Relationship, Drug
• Fas Ligand Protein
• Gene Deletion
• Humans
• Membrane Glycoproteins (metabolism)
• Mice
• Mutagenesis, Site-Directed
• Point Mutation
• Protein Structure, Tertiary
• Recombinant Proteins (metabolism)
• Signal Transduction
• Time Factors
• Tumor Cells, Cultured
• cdc42 GTP-Binding Protein (chemistry, genetics, metabolism)
• fas Receptor (metabolism)