Inhibition of host kinase activity altered by the LMP2A signalosome-a therapeutic target for Epstein-Barr virus latency and associated disease.
Epstein-Barr virus (EBV) is a human herpesvirus that establishes a lifelong latent infection in the majority of the human population. The virus resides in a latent state in B lymphocytes and is associated with a variety of cancers in the human host. In normal individuals, latent infection with EBV typically poses no health risk, but upon immunosuppression, either following organ transplantation or HIV infection, malignancies and lymphoproliferative diseases can result. Latent membrane protein 2A (LMP2A) is a virally encoded membrane protein that is expressed in EBV latent infection and in most of the tumors associated with EBV infection. Previous studies have indicated that LMP2A expression alters the activity of the Src family protein tyrosine kinases, the Syk protein tyrosine kinase, the Btk protein tyrosine kinase, and phosphatidylinositol 3-kinase (PI3-kinase). In this study, inhibitors of each of these kinases were tested using an in vitro system dependent on LMP2A expression for B cell colony formation in IL-7 containing methylcellulose media. Of the inhibitors tested, only piceatannol, a Syk tyrosine kinase inhibitor, demonstrated a specific effect on LMP2A expressing cells and not control cells. These studies provide a basis for targeting LMP2A function in EBV latency and may allow for the identification of novel therapeutics for the treatment or eradication of EBV latent infections and associated proliferative disorders.
Cooper
Lori
L
Department of Microbiology and Immunology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.
Longnecker
Richard
R
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000577:Amides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology; D001854:Bone Marrow Cells / Q000166:cytology; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology; D000072377:Syk Kinase; D014763:Viral Matrix Proteins / Q000378:metabolism*; D017735:Virus Latency / Q000502:physiology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000577:Amides; D002867:Chromones; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D013267:Stilbenes; D000072377:Syk Kinase; D014763:Viral Matrix Proteins; D019061:src-Family Kinases; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C118451:LFM A13; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C041525:3,3',4,5'-tetrahydroxystilbene; C000625949:BTK protein, human; C000606896:SYK protein, human; C000606897:Syk protein, mouse