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Molecular and Cellular Biology, August 2003, p. 5716-5725, Vol. 23, No. 16
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.16.5716-5725.2003

Caspase 3-Mediated Inactivation of Rac GTPases Promotes Drug-Induced Apoptosis in Human Lymphoma Cells

Baolin Zhang,* Yaqin Zhang, and Emily Shacter

Laboratory of Biochemistry, Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892

Received 14 March 2003/ Accepted 13 May 2003

The Rac members of the Rho family GTPases control signaling pathways that regulate diverse cellular activities, including cytoskeletal organization, gene transcription, and cell transformation. Rac is implicated in apoptosis, but little is known about the mechanism by which it responds to apoptotic stimuli. Here we demonstrate that endogenous Rac GTPases are caspase 3 substrates that are cleaved in human lymphoma cells during drug-induced apoptosis. Cleavage of Rac1 occurs at two unconventional caspase 3 sites, VVGD11/G and VMVD47/G, and results in inactivation of the GTPase and effector functions of the protein (binding to the p21-activated protein kinase PAK1). Expression of caspase 3-resistant Rac1 mutants in the cells suppresses drug-induced apoptosis. Thus, proteolytic inactivation of Rac GTPases represents a novel, irreversible mechanism of Rac downregulation that allows maximal cell death following drug treatment.

* Corresponding author. Mailing address: Laboratory of Biochemistry, Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, HFM-535, 29 Lincoln Dr., Building 29A, Room 2B-24, Bethesda, MD 20892-4555. Phone: (301) 827-1784. Fax: (301) 480-3256. E-mail: zhangb{at}cber.fda.gov.

Molecular and Cellular Biology, August 2003, p. 5716-5725, Vol. 23, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.16.5716-5725.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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