title: B-cell activating factor-receptor specific activation of tumor necrosis factor receptor associated factor 6 and the phosphatidyl inositol 3-kinase pathway in lymphoma B cells.
abstract: B-cell activating factor-receptor (BAFF-R) is the primary BAFF receptor that is responsible for promoting B-cell development and survival. Malignant B-cells exploit the BAFF/BAFF-R system, and high serum BAFF levels or genetic alterations in BAFF receptors have been found in B-cell cancers. BAFF signaling impacts pro-survival pathways. However, other than nuclear factor-κB2 (NF-κB2), little is known about the specific pathways activated by individual BAFF receptors. Using a novel BAFF-R expression model we have demonstrated that activation of BAFF-R, independent of transmembrane activator and cytophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA), can induce phosphorylation of Akt and glycogen synthase kinase 3β (GSK3β). Expression of an activated form of BAFF-R also enhanced a pro-survival gene expression pattern, including the novel BAFF-regulated gene Pin1, whose expression was phosphatidyl inositol 3-kinase (PI3K)-dependent. Additionally, we showed that TRAF6 is essential for mediating BAFF-R dependent activation of Akt. Together these data describe a novel role for TRAF6 in BAFF-R-specific activation of the PI3K pathway and provide evidence suggesting a new role for Pin1 in BAFF-R signaling.
authors.affiliation: Division of Hematology, Mayo Clinic , Rochester, MN , USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Secreto
authors.forename: Michelle
authors.initials: M
authors.lastname: Manske
authors.forename: Tammy
authors.initials: T
authors.lastname: Price-Troska
authors.forename: Steven
authors.initials: S
authors.lastname: Ziesmer
authors.forename: Lucy S
authors.initials: LS
authors.lastname: Hodge
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Novak
mesh_terms: D053264:B-Cell Activating Factor / Q000494:pharmacology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*
chemical_list: D053264:B-Cell Activating Factor; D019948:Receptors, Interleukin-4; D048029:TNF Receptor-Associated Factor 6; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: BAFF; BAFF-R; PI3K; lymphoma