Epstein-Barr virus latent membrane protein 2A (LMP2A) employs the SLP-65 signaling module.
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-gamma2 (PLC-gamma2) 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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, B-Lymphocytes, Base Sequence, Carrier Proteins, Cell Line, DNA Primers, Enzyme Inhibitors, Enzyme Precursors, Epstein-Barr Virus Infections, Female, Herpesvirus 4, Human, Humans, Hydrogen Peroxide, Intracellular Signaling Peptides and Proteins, Isoenzymes, Male, Mice, Mice, Knockout, Mice, Transgenic, Nuclear Proteins, Phospholipase C gamma, Phosphoproteins, Phosphorylation, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Signal Transduction, Type C Phospholipases, Tyrosine, Vanadates, Viral Matrix Proteins
Adaptor Proteins, Signal Transducing, Animals, B-Lymphocytes, Base Sequence, Carrier Proteins, Cell Line, DNA Primers, Enzyme Inhibitors, Enzyme Precursors, Epstein-Barr Virus Infections, Female, Herpesvirus 4, Human, Humans, Hydrogen Peroxide, Intracellular Signaling Peptides and Proteins, Isoenzymes, Male, Mice, Mice, Knockout, Mice, Transgenic, Nuclear Proteins, Phospholipase C gamma, Phosphoproteins, Phosphorylation, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Signal Transduction, Type C Phospholipases, Tyrosine, Vanadates, Viral Matrix Proteins
J. Exp. Med.
Date: Aug. 06, 2001
PubMed ID: 11489945
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