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First published on December 30, 2005; DOI: 10.1124/mol.105.019364

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Received for publication October 11, 2005.
Revised November 29, 2005.
Accepted for publication December 29, 2005.

Use of penetrating peptides interacting with PP1/PP2A proteins as a general approach for a drug phosphatase technology

Julien Guergnon 1, Frederic Dessauge 2, Victoria Dominguez 2, Jean Viallet 3, Serge Bonnefoy 2, Victor j Yuste 2, Odile Mercereau-Puijalon 4, Xavier Cayla 5, angelita Rebollo 2, Santos A Susin 2, pierre-Etienne Bost 2, Alphonse Garcia 1*

1 institut pasteur 2 Institut Pasteur 3 LEDAC UMR CNRS 5538 4 institut Pasteur 5 UMR 6175 INRA-CNRS

* Address correspondence to: E-mail: agarcia{at}pasteur.fr

Abstract

Type 1 (PP1) and type 2A (PP2A) represent two major families of serine/threonine protein phosphatases that have been implicated in the regulation of many cellular processes including cell growth and apoptosis in mammalian cells. PP1 and PP2A proteins are composed of oligomeric complexes comprising a catalytic structure (PP1c or PP2AC) containing the enzymatic activity and at least one more interacting subunit. The binding of different subunits to a catalytic structure generates a broad variety of holoenzymes. We showed here that Casein Kinase 2{alpha} (Ck2{alpha}) and SV40 virus small t antigen share a putative common {beta}-strand structure required for PP2A1 trimeric holoenzyme binding. We have also characterized DPT-sh1, a short basic peptide from Ck2{alpha} that only interacted in vitro with PP2A-A subunit and behaves as a non toxic penetrating shuttle in several cultivated human cell lines and chick embryos. In addition, DPT-sh1 specifically accumulated in human red cells infected with P. falciparum malaria parasites. We therefore designed bipartite peptides containing DPT-sh1 and PP1 or PP2A interacting sequences. We found that DPT-5, a DPT-sh1-derived peptide containing a short sequence identified in CD28 antigen, interacts with PP2A-B{alpha} and DPT-7, another DPT-sh1-derived peptide containing a short sequence identified in Bad as a PP1 catalytic consensus docking motif, induce apoptosis in cultivated cell lines. These results clearly indicate that the rational design of PP1/PP2A interacting peptides is a pertinent strategy to deregulate intracellular survival pathways.


Key words: Protein ser/thr Phosphatases, Phosphorylation/Dephosphorylation


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[Abstract] [Full Text] [PDF]


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