title: Integral membrane protein 2 of Epstein-Barr virus regulates reactivation from latency through dominant negative effects on protein-tyrosine kinases.
abstract: An Epstein-Barr virus-encoded protein, LMP2, blocks the effects of surface immunoglobulin (slg) cross-linking on calcium mobilization and on lytic reactivation of EBV in latently infected and growth-transformed primary human B lymphocytes. In wild-type EBV-transformed cells, LMP2 is constitutively tyrosine phosphorylated and is associated with Lyn and Syk protein-tyrosine kinases (PTKs). Baseline Lyn PTK activity is substantially reduced, and slg cross-linking fails to activate Lyn, Syk, Pl3-K, PLC gamma 2, Vav, Shc, and MAPK. Syk, Pl3-K, PLC gamma 2, and Vav are constitutively tyrosine phosphorylated, and their tyrosine phosphorylation does not change following slg cross-linking. In contrast, cross-linking slg on cells transformed by LMP2 null mutant EBV recombinants triggers the same protein tyrosine kinase cascade as in noninfected B lymphocytes. These data are consistent with a model in which LMP2 is a constitutive dominant negative modulator of slg receptor signaling through its effects on Lyn, Syk, or regulators of these kinases.
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: C L
authors.initials: CL
authors.lastname: Miller
authors.forename: A L
authors.initials: AL
authors.lastname: Burkhardt
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.forename: B
authors.initials: B
authors.lastname: Stealey
authors.forename: R
authors.initials: R
authors.lastname: Longnecker
authors.forename: J B
authors.initials: JB
authors.lastname: Bolen
authors.forename: E
authors.initials: E
authors.lastname: Kieff
mesh_terms: D000956:Antigens, Viral / Q000378:metabolism* / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D004789:Enzyme Activation; D004854:Herpesvirus 4, Human / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000956:Antigens, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins; D011505:Protein-Tyrosine Kinases