pervanadate and Epstein-Barr-Virus-Infections

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.

Topics: 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; Syk Kinase; Type C Phospholipases; Tyrosine; Vanadates; Viral Matrix Proteins