WW- and SH3-Domain Interactions with Epstein-Barr Virus LMP2A

Longnecker, Richard; Merchant, Mark; Brown, Melissa E.; Fruehling, Sara; Bickford, James O.; Ikeda, Masato; Harty, Ronald N.

doi:10.1006/excr.2000.4900

Cited by 29 publications

(22 citation statements)

References 52 publications

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“…Chief among these is the RING-H2-finger domain that could facilitate protein -protein interaction(s) leading to the degradation of specific substrate(s) involved in oncogenesis and the PY motif that could bind to WW domain proteins, including several HECTtype E3 ligases such as NEDD4, AIP4 and Smurf2. The PPPPY motif sequence of RNF11 is identical to that of Smads 2, 3 and 7, which have been shown to bind WW domains of Smurf2 Ub ligase and mediate the ubiquitination and degradation of various target proteins (Coopman et al, 2000;Longnecker et al, 2000). Smurf2 plays a key role in the ubiquitination and proteasomal degradation of receptor-activated Smad2 and Smad3, and corepressor SnoN (Bonni et al, 2001;Mizuide et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

The RING-H2 protein RNF11 is overexpressed in breast cancer and is a target of Smurf2 E3 ligase

et al. 2003

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The breast cancer-associated T2A10 clone was originally isolated from a cDNA library enriched for tumour messenger ribonucleic acids. Our survey of 125 microarrayed primary tumour tissues using affinity purified polyclonal antibodies has revealed that corresponding protein is overexpressed in invasive breast cancer and is weakly expressed in kidney and prostate tumours. Now known as RNF11, the gene encodes a RING-H2 domain and a PY motif, both of which mediate protein -protein interactions. In particular, the PPPPY sequence of RNF11 PY motif is identical to that of Smad7, which has been shown to bind to WW domains of Smurf2, an E3 ubiquitin ligase that mediates the ubiquitination and degradation of the TGFb receptor complex. Using various mutants of RNF11 in GST pulldown and immunoprecipitation assays, we found that RNF11 interacts with Smurf2 through the PY motif, leading to ubiquitination of both proteins. Smurf2 plays an active role in the repression of TGFb signalling, and our data indicate that overexpression of RNF11, through its interaction with Smurf2, can restore TGFb responsiveness in transfected cells.

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Section: Discussionmentioning

confidence: 99%

The RING-H2 protein RNF11 is overexpressed in breast cancer and is a target of Smurf2 E3 ligase

et al. 2003

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“…Similar strategies have been employed by other ␥-herpesviruses to manipulate B-cell signaling events to induce cell activation, proliferation, survival, and differentiation. For example, the LMP-2A protein of EBV imitates a constitutively activated B-cell receptor (7,8), whereas another oncogenic EBV protein LMP-1 mimics a deregulated CD40 receptor, which is a co-receptor of the B-cell receptor (5,6,40). Although EBV manipulates the B-cell-signaling events at receptor levels via LMP-1 and LMP-2A, MHV-68 influences the signaling molecule downstream of the B-cell receptor via M2, which functions as an activator of Vav.…”

Section: Volume 280 • Number 45 • November 11 2005mentioning

confidence: 99%

“…This viral protein binds and activates TRAF-2 and -3 proteins leading to NF-B activation and consequently cell proliferation (5,6). It has been demonstrated that LMP-2A associates with the cellular tyrosine kinases Fyn, Lyn, and Syk, modulating their interactions with the B-cell receptor (7,8), thereby acting in the same manner as a constitutively active B-cell receptor. In B-cell receptor-negative B-cells, LMP-2A activates signals that are usually generated by the B-cell receptor to inhibit apoptosis of infected cells (9).…”

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confidence: 99%

Murine γ-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

Madureira

Matos

Soeiro

et al. 2005

Journal of Biological Chemistry

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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.

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“…The amino-terminal domain of this viral protein contains eight tyrosines that associate with the cellular protein tyrosine kinases Lyn and Syk via SH2-phosphotyrosine interactions and five proline-rich regions, three of which possess the PxxP core consensus sequence required for interacting with SH3 domains and two of which possess the PPxY core consensus sequence (PY motif) required for interacting with proteins containing WW modules (reviewed in Longnecker et al, 2000). In screening for proteins interacting with the PY domains, two laboratories have independently identified members of the Nedd4 ubiquitin ligase family Winberg et al, 2000).…”

Section: The Rescue Program: Lmp-2a and The Capture Of Cellular Ubiqumentioning

confidence: 99%

Epstein–Barr virus oncogenesis and the ubiquitin–proteasome system

Masucci

2004

Oncogene

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Epstein-Barr virus (EBV), a human herpesvirus associated with lymphoid and epithelial cell tumors, encodes several proteins that exploit the ubiquitin-proteasome system to regulate latency and allow the persistence of infected cells in immunocompetent hosts. Further modifications of ubiquitin-dependent proteolysis by activated cellular oncogenes contribute to malignant transformation. A detailed understanding of these processes may lead to the development of new therapeutic strategies for EBVassociated cancers.

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WW- and SH3-Domain Interactions with Epstein-Barr Virus LMP2A

Cited by 29 publications

References 52 publications

The RING-H2 protein RNF11 is overexpressed in breast cancer and is a target of Smurf2 E3 ligase

The RING-H2 protein RNF11 is overexpressed in breast cancer and is a target of Smurf2 E3 ligase

Murine γ-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

Epstein–Barr virus oncogenesis and the ubiquitin–proteasome system

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