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 Previous Article

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{triangledown} ,{dagger}

Maxime Hallé,1 Ying-Chih Liu,2 Serge Hardy,1 Jean-François Théberge,1 Christophe Blanchetot,3 Annie Bourdeau,1 Tzu-Ching Meng,2* and Michel L. Tremblay1*

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.

* Corresponding author. Mailing address for Tzu-Ching Meng: Institute of Biological Chemistry, Academia Sinica, 128 Academia Road, Section 2, Nankang 115, Taipei, Taiwan. Phone: 886-2-27855696, ext. 6140. Fax: 886-2-27889759. E-mail: tcmeng{at}gate.sinica.edu.tw. Mailing address for Michel L. Tremblay: McGill Cancer Center, McGill University, 3655 Promenade Sir-William-Osler, Room 701, Montréal, Québec H3G 1Y6, Canada. Phone: (514) 398-8480. Fax: (514) 398-6769. E-mail: michel.tremblay{at}mcgill.ca.

{triangledown} Published ahead of print on 27 November 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

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.



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