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Cited by 60Viral-associated cancers and disordersNF-κB Signaling PathwaysT-cell and B-cell Immunology

Epstein-Barr Virus Latent Membrane Protein 2a (Lmp2a) Employs the Slp-65 Signaling Module

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Engels, Niklas, Merchant, Mark, Pappu, Rajita, Chan, Andrew C., Longnecker, Richard, Wienands, Jürgen·2001·The Journal of Experimental Medicine
DOI 10.1084/jem.194.3.255PMC PMC2193464
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Abstract

In latently infected B lymphocytes, the Epstein-Barr virus (EBV) suppresses signal transduction from the antigen receptor through expression of the integral latent membrane protein 2A (LMP2A). At the same time, LMP2A triggers B cell survival by a yet uncharacterized maintenance signal that is normally provided by the antigen receptor. The molecular mechanisms are unknown as LMP2A-regulated signaling cascades have not been described so far. Using a novel mouse model we have identified the intracellular adaptor protein Src homology 2 (SH2) domain–containing leukocyte protein (SLP)-65 as a critical downstream effector of LMP2A in vivo. Biochemical analysis of the underlying signaling pathways revealed that EBV infection causes constitutive tyrosine phosphorylation of one of the two SLP-65 isoforms and complex formation between SLP-65 and the protooncoprotein CrkL (CT10 regulator of kinase like). This leads to antigen receptor-independent phosphorylation of Cbl (Casitas B lineage lymphoma) and C3G. In contrast, phospholipase C-γ2 (PLC-γ2) activation is completely blocked. Our data show that in order to establish a latent EBV infection, LMP2A selectively activates or represses SLP-65–regulated signaling pathways.

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  • PLCγ2 and its BCR-associated signaling are blocked via the virally encoded integral latent membrane protein 2A in combination with BLNK.

    “It was noted that PLCγ2 and its BCR-associated signaling are blocked via the virally encoded integral latent membrane protein 2A in combination with BLNK (140).”

    From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [140]

    The Introduction identifies BLNK as SLP-65, and the Results report that EBV infection uncouples SLP-65 phosphorylation from PLC-γ2 activation, explaining a block in BCR-induced signaling in LMP2A-expressing cells. But the Results say the mechanism remains unknown; the paper does not establish that LMP2A and BLNK act in combination to cause the block. (LLM, conf=0.84)

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References 67 · Cited by 60

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Authors
Engels, N., Merchant, M., Pappu, R., Chan, A. C., Longnecker, R., & Wienands, J.
Affiliations
  • Bielefeld University (DE)
  • Northwestern University (US)
  • Howard Hughes Medical Institute (US)
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2001-07-30
Volume
194
Issue
3
Pages
255-264
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.194.3.255
PMC
PMC2193464
OpenAlex
W2139098343
Cited by
60
References
67
Citations by year
2026: 2 · 2025: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 2 · 2017: 1 · 2015: 4 · 2014: 1 · 2013: 1 · 2012: 3
FWCI
3.25
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (R01CA062234, R01CA073507, CA 73507, CA62234)
  • National Institute of Dental and Craniofacial Research (R01DE013127, DE 13127)
Topics
  • Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
Epstein-Barr virus, LMP2A, CRKL, CBL, C3G, PLCγ2, antigen receptor signaling, B cell survival, viral latency, tyrosine phosphorylation, adaptor proteins, B cells
MeSH terms
Syk Kinase, Animals, B-Lymphocytes, Base Sequence, Carrier Proteins, Cell Line, Enzyme Inhibitors, Enzyme Precursors, Herpesvirus 4, Human, Female, Humans, Hydrogen Peroxide, Isoenzymes, Male, Mice, Transgenic, Nuclear Proteins, Type C Phospholipases, Phosphoproteins, Phosphorylation, Protein-Tyrosine Kinases, Tyrosine, Vanadates, Viral Matrix Proteins, Signal Transduction, Protein Tyrosine Phosphatases, DNA Primers, Mice, Knockout, Epstein-Barr Virus Infections, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, Phospholipase C gamma

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