HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 45, 37310-37318, November 11, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/45/37310    most recent M507478200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Madureira, P. A. Articles by Lam, E. W.-F. Search for Related Content PubMed PubMed Citation Articles by Madureira, P. A. Articles by Lam, E. W.-F. Social Bookmarking                      What's this?

Murine -Herpesvirus 68 Latency Protein M2 Binds to Vav Signaling Proteins and Inhibits B-cell Receptor-induced Cell Cycle Arrest and Apoptosis in WEHI-231 B Cells^*

Patrícia A. Madureira12, Paulo Matos¶, Inês Soeiro1, Linda K. Dixon||, J. Pedro Simas3, and Eric W.-F. Lam4

From the Cancer Research-UK Laboratories, Department of Cancer Medicine, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom, the Instituto Gulbenkian de Ciência, Rua de Quinta Grande 6, 2780-156 Oeiras and Instituto de Microbiologia, Faculdade de Medicina, Universidade de Lisboa, Portugal, the ^¶Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Avenida Padre Cruz, 1649–016 Lisboa, Portugal, and the ^||Institute for Animal Health, Pirbright, Woking, Surrey GU24 ONF, United Kingdom

The MHV-68 latent protein, M2, does not have homology to any known viral or cellular proteins, and its function is unclear. To define the role played by M2 during MHV-68 latency as well as the molecular mechanism involved, we used M2 as bait to screen a yeast two-hybrid mouse B-cell cDNA library. Vav1 was identified as an M2-interacting protein in two independent screenings. Subsequent yeast two-hybrid interaction studies showed that M2 also binds to Vav2, but not Vav3, and that three "PXXP" motifs located at the C terminus of M2 are important for this interaction. The interactions between M2 and Vav proteins were also confirmed in vivo in 293T and WEHI-231 B-cells by co-immunoprecipitation assays. Rac1/GST-PAK "pull-down" experiments and Western blot analysis using a phospho-Vav antibody demonstrated that expression of M2 in WEHI-231 cells enhances Vav activity. We further showed in WEHI-231 cells that M2 expression promotes proliferation and survival and is associated with enhanced cyclin D2 and repressed p27^Kip1, p130, and Bim expression. Taken together, these experiments suggest that M2 might have an important role in disseminating the latent virus during the establishment and maintenance of latency by modulating B-cell receptor-mediated signaling events through Vav to promote B-cell activation, proliferation, and survival.

Received for publication, July 11, 2005 , and in revised form, September 1, 2005.

^* This work was supported in part by a short term fellowship from the European Molecular Biology Organization (to P. M.) and by Portuguese Fundação para a Ciência e Tecnologia Grant POCTI/ESP/34240/2000 (to J. P. S.). 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.

¹ Recipients of fellowships from Fundação para a Ciência e a Tecnologia, Portugal.

² To whom correspondence may be addressed. Tel.: 44-20-8383-5829; Fax: 44-20-8383-5830; E-mail: p.madureira{at}imperial.ac.uk. ³ To whom correspondence may be addressed. Tel.: 351-21-7999510; Fax: 351-21-7999459; E-mail: jpsimas{at}igc.gulbenkian.pt. ⁴ Supported by the Leukaemia Research Fund, the Engineering and Physical Sciences Research Council, and Cancer Research-UK. To whom correspondence may be addressed. Tel.: 44-20-8383-5829; Fax: 44-20-8383-5830; E-mail: eric.lam{at}imperial.ac.uk.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. C. Forrest and S. H. Speck Establishment of B-Cell Lines Latently Infected with Reactivation-Competent Murine Gammaherpesvirus 68 Provides Evidence for Viral Alteration of a DNA Damage-Signaling Cascade J. Virol., August 1, 2008; 82(15): 7688 - 7699. [Abstract] [Full Text] [PDF]

				J. H. Herskowitz, A. M. Siegel, M. A. Jacoby, and S. H. Speck Systematic Mutagenesis of the Murine Gammaherpesvirus 68 M2 Protein Identifies Domains Important for Chronic Infection J. Virol., April 1, 2008; 82(7): 3295 - 3310. [Abstract] [Full Text] [PDF]

				L. Rodrigues, M. Pires de Miranda, M. J. Caloca, X. R. Bustelo, and J. P. Simas Activation of Vav by the Gammaherpesvirus M2 Protein Contributes to the Establishment of Viral Latency in B Lymphocytes. J. Virol., June 1, 2006; 80(12): 6123 - 6135. [Abstract] [Full Text] [PDF]