title: BAFF activates Erk1/2 promoting cell proliferation and survival by Ca2+-CaMKII-dependent inhibition of PP2A in normal and neoplastic B-lymphoid cells.
abstract: B-cell activating factor (BAFF) is involved in not only the physiology of normal B cells, but also the pathophysiology of aggressive B cells related to malignant and autoimmune diseases. However, how excessive BAFF promotes aggressive B-cell proliferation and survival is not well understood. Here we show that excessive human soluble BAFF (hsBAFF) enhanced cell proliferation and survival in normal and B-lymphoid (Raji) cells, which was associated with suppression of PP2A, resulting in activation of Erk1/2. This is supported by the findings that pretreatment with U0126 or PD98059, expression of dominant negative MKK1, or overexpression of PP2A prevented hsBAFF-induced activation of Erk1/2 and cell proliferation/viability in the cells. It appears that hsBAFF-mediated PP2A-Erk1/2 pathway and B-cell proliferation/viability was Ca(2+)-dependent, as pretreatment with BAPTA/AM, EGTA or 2-APB significantly attenuated these events. Furthermore, we found that inhibiting CaMKII with KN93 or silencing CaMKII also attenuated hsBAFF-mediated PP2A-Erk1/2 signaling and B-cell proliferation/viability. The results indicate that BAFF activates Erk1/2, in part through Ca(2+)-CaMKII-dependent inhibition of PP2A, increasing cell proliferation/viability in normal and neoplastic B-lymphoid cells. Our data suggest that inhibitors of CaMKII and Erk1/2, activator of PP2A or manipulation of intracellular Ca(2+) may be exploited for prevention of excessive BAFF-induced aggressive B-cell malignancies and autoimmune diseases.
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China.
authors.forename: Dingfang
authors.initials: D
authors.lastname: Liang
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China.
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Gui
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China.
authors.forename: Chong
authors.initials: C
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China.
authors.forename: Sujuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China.
authors.forename: Shuangquan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA; Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. Electronic address: shuan1@lsuhsc.edu.
authors.forename: Shile
authors.initials: S
authors.lastname: Huang
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China. Electronic address: lchen@njnu.edu.cn.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats
chemical_list: D053264:B-Cell Activating Factor; D047428:Protein Kinase Inhibitors; C505719:TNFSF13B protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054648:Protein Phosphatase 2; D002118:Calcium
keywords: 1,2-bis(o-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) ester; 2-APB; 2-aminoethoxydiphenyl borate; B cell maturation antigen; B cells; B lymphocyte stimulator; B-cell activating factor of the TNF family; BAFF; BAPTA/AM; BCMA; BLyS; CRAC; Ca(2+)-release activated Ca(2+); CaM; CaMKII; Calcium ion; EGTA; ER; Erk1/2; FBS; MAPK; MEK; PBS; PP2A; RA; SLE; SS; Sjögren's syndrome; TACI; TALL-1; THANK; TNF and apoptosis ligand-related leukocyte-expressed ligand1; TNF homologue that activates apoptosis, nuclear factor κB, and c-Jun NH2-terminal kinase; calcium/calmodulin-dependent protein kinase II; calmodulin; endoplasmic reticula; ethylene glycol tetra-acetic acid; extracellular signal-related kinase 1/2; fetal bovine serum; mitogen-activated protein kinase; mitogen-activated protein kinase kinase; phosphate buffered saline; protein phosphatases 2A; rheumatoid arthritis; systemic lupus erythematosus; transmembrane activator and cyclophilin ligand interactor