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Molecular and Cellular Biology, February 2007, p. 1172-1190, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.02462-05
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Caspase-3 Regulates Catalytic Activity and Scaffolding Functions of the Protein Tyrosine Phosphatase PEST, a Novel Modulator of the Apoptotic Response ^,

Department of Biochemistry and McGill Cancer Center, McGill University, McIntyre Medical Sciences Building, 3655 Promenade Sir-William-Osler, Montréal, Québec H3G 1Y6, Canada,¹ Institute of Biological Chemistry, Academia Sinica, 128 Academia Road, Section 2, Nankang, 105 Taipei, Taiwan, Republic of China,² Department of Cell Biology, Utrecht University, Psadualaan 8, 3584CH Utrecht, The Netherlands³

Received 23 December 2005/ Returned for modification 16 March 2006/ Accepted 6 November 2006

The protein tyrosine phosphatase PEST (PTP-PEST) is involved in the regulation of the actin cytoskeleton. Despite the emerging functions attributed to both PTPs and the actin cytoskeleton in apoptosis, the involvement of PTP-PEST in apoptotic cell death remains to be established. Using several cell-based assays, we showed that PTP-PEST participates in the regulation of apoptosis. As apoptosis progressed, a pool of PTP-PEST localized to the edge of retracting lamellipodia. Expression of PTP-PEST also sensitized cells to receptor-mediated apoptosis. Concertedly, specific degradation of PTP-PEST was observed during apoptosis. Pharmacological inhibitors, immunodepletion experiments, and in vitro cleavage assays identified caspase-3 as the primary regulator of PTP-PEST processing during apoptosis. Caspase-3 specifically cleaved PTP-PEST at the ⁵⁴⁹DSPD motif and generated fragments, some of which displayed increased catalytic activity. Moreover, caspase-3 regulated PTP-PEST interactions with paxillin, leupaxin, Shc, and PSTPIP. PTP-PEST acted as a scaffolding molecule connecting PSTPIP to additional partners: paxillin, Shc, Csk, and activation of caspase-3 correlated with the modulation of the PTP-PEST adaptor function. In addition, cleavage of PTP-PEST facilitated cellular detachment during apoptosis. Together, our data demonstrate that PTP-PEST actively contributes to the cellular apoptotic response and reveal the importance of caspases as regulators of PTPs in apoptosis.

Published ahead of print on 27 November 2006.

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