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J. Biol. Chem., Vol. 279, Issue 24, 25905-25915, June 11, 2004

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Activation of Adenovirus Type 2 Early Region 4 ORF4 Cytoplasmic Death Function by Direct Binding to Src Kinase Domain^*

Claudia Champagne, Marie-Claude Landry, Marie-Claude Gingras, and Josée N. Lavoie¶

From the Centre de Recherche en Cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, CHUQ, Québec G1R 2J6, Canada

Adenovirus type 2 (Ad2) early region 4 ORF4 (E4orf4) triggers a major death pathway that requires its accumulation in cellular membranes and its tyrosine phosphorylation. This program is regulated by Src family kinases and triggers a potent ZVAD (benzyloxycarbonyl-VAD)- and Bcl2-resistant cell death response in human-transformed cells. How E4orf4 deregulates Src-dependent signaling is unknown. Here we provide strong evidence that a physical interaction requiring the kinase domain of Src and the arginine-rich motif of E4orf4 is involved. The Src binding domain of E4orf4 overlaps with, but is distinct from that of the B subunit of protein phosphatase 2A (PP2A-B) and some E4orf4 complexes contain both PP2A and Src. Functional assays using mutant E4orf4 revealed that deregulation of Src signaling, activation of the Jun kinase pathway, and cell blebbing were all critically dependent on Src binding. In contrast, PP2A-B binding per se was not required to engage the Src-dependent death pathway but was more critical for triggering a distinct death activity. Both E4orf4 death activities were manifested within a given cell population, were typified by distinct morphological features, and contributed to overall cell killing, although to different extents in various cell types. We conclude that E4orf4 binding to the Src kinase domain leads to deregulation of Src signaling and plays a crucial role in induction of the cytoplasmic death pathway. Nonetheless, both Src and PP2A enzymes are critical targets of E4orf4 that likely cooperate to trigger E4orf4-induced tumor cell killing and whose relative contributions may vary in function of the cellular background.

Received for publication, January 28, 2004 , and in revised form, April 2, 2004.

^* This work was supported by Grant MOP-49450 (to J. N. L.) from the Canadian Institutes of Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a studentship from the National Sciences and Engineering Research Council of Canada.

Recipient of a studentship from the Canadian Institutes of Health Research.

^¶ A Junior 2 Scholar from the Fond de la Recherche en Santé du Québec (FRSQ). To whom correspondence should be addressed: CRC, L'Hôtel-Dieu de Québec, CHUQ, St-Patrick, 9 Rue McMahon, Québec G1R 2J6, Canada. Tel.: 418-525-4444, ext. 15120; Fax: 418-691-5439; E-mail: josee.lavoie{at}crhdq.ulaval.ca.

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