title: Src kinase and Syk activation initiate PI3K signaling by a chimeric latent membrane protein 1 in Epstein-Barr virus (EBV)+ B cell lymphomas.
abstract: The B lymphotrophic γ-herpesvirus EBV is associated with a variety of lymphoid- and epithelial-derived malignancies, including B cell lymphomas in immunocompromised and immunosuppressed individuals. The primary oncogene of EBV, latent membrane protein 1 (LMP1), activates the PI3K/Akt pathway to induce the autocrine growth factor, IL-10, in EBV-infected B cells, but the mechanisms underlying PI3K activation remain incompletely understood. Using small molecule inhibition and siRNA strategies in human B cell lines expressing a chimeric, signaling-inducible LMP1 protein, nerve growth factor receptor (NGFR)-LMP1, we show that NGFR-LMP1 utilizes Syk to activate PI3K/Akt signaling and induce IL-10 production. NGFR-LMP1 signaling induces phosphorylation of BLNK, a marker of Syk activation. Whereas Src kinases are often required for Syk activation, we show here that PI3K/Akt activation and autocrine IL-10 production by NGFR-LMP1 involves the Src family kinase Fyn. Finally, we demonstrate that NGFR-LMP1 induces phosphorylation of c-Cbl in a Syk- and Fyn-dependent fashion. Our results indicate that the EBV protein LMP1, which lacks the canonical ITAM required for Syk activation, can nevertheless activate Syk, and the Src kinase Fyn, resulting in downstream c-Cbl and PI3K/Akt activation. Fyn, Syk, and PI3K/Akt antagonists thus may present potential new therapeutic strategies that target the oncogene LMP1 for treatment of EBV+ B cell lymphomas.
authors.affiliation: Program in Immunology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Olivia
authors.initials: O
authors.lastname: Hatton
authors.forename: Stacie L
authors.initials: SL
authors.lastname: Lambert
authors.forename: Sheri M
authors.initials: SM
authors.lastname: Krams
authors.forename: Olivia M
authors.initials: OM
authors.lastname: Martinez
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000821:virology*; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D047908:Intracellular Signaling Peptides and Proteins; D020800:Receptor, Nerve Growth Factor; D011994:Recombinant Proteins; D014763:Viral Matrix Proteins; D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051076:Proto-Oncogene Proteins c-fyn; C000606896:SYK protein, human; D000072377:Syk Kinase; D019061:src-Family Kinases