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Journal of Virology, May 1999, p. 3587-3594, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Cleavage of RasGAP and Phosphorylation of Mitogen-Activated Protein Kinase in the Course of Coxsackievirus B3 Replication

Michael Huber,1,dagger Kathleen A. Watson,2 Hans-Christoph Selinka,1 Christopher M. Carthy,2 Karin Klingel,1 Bruce M. McManus,2 and Reinhard Kandolf1,*

Department of Molecular Pathology, Institute for Pathology, University of Tübingen, D-72076 Tübingen, Germany,1 and Department of Pathology and Laboratory Medicine, University of British Columbia- St. Paul's Hospital, Vancouver, British Columbia, Canada2

Received 1 September 1998/Accepted 26 January 1999

Recently, we reported on tyrosine phosphorylation of distinct cellular proteins in the course of enterovirus infections (M. Huber, H.-C. Selinka, and R. Kandolf, J. Virol. 71:595-600, 1997). These phosphorylation events were mediated by Src-like kinases and were shown to be necessary for effective virus replication. That study is now extended by examination of the interaction of the adapter protein Sam68, a cellular target of Src-like kinases which has been shown to interact with the poliovirus 3D polypeptide, with cellular signaling proteins as well as the function of the latter during infection. Here, we report that the RNA-binding and protein-binding protein Sam68 associates with the p21ras GTPase-activating protein RasGAP. Remarkably, RasGAP is cleaved during infections with different strains of coxsackievirus B3 as well as with echovirus 11 and echovirus 12, yielding a 104-kDa protein fragment. This cleavage event, which cannot be prevented by the general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, may promote the activation of the Ras pathway, as shown by the activating dual phosphorylation of the mitogen-activated protein kinases Erk-1 and Erk-2 in the late phase of infection. Moreover, downstream targets of the mitogen-activated protein kinases, i.e., the p21ras exchange factor Sos-1 and cytoplasmic phospholipase A2, are phosphorylated with parallel time courses during infection. Activation or inhibition of cellular signaling pathways may play a general role in regulating effective enterovirus replication and pathogenesis, and the results of this study begin to unravel the molecular cross talk between enterovirus infection and key cellular signaling networks.

* Corresponding author. Mailing address: Abteilung fuer Molekulare Pathologie, Universität Tübingen, Liebermeisterstr. 8, D-72076 Tübingen, Germany. Phone: 49-7071-2982264. Fax: 49-7071-295334. E-mail: reinhard.kandolf{at}med.uni-tuebingen.de.

dagger Present address: The Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

Journal of Virology, May 1999, p. 3587-3594, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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