title: Point mutations of 3BP2 identified in human-inherited disease cherubism result in the loss of function.
abstract: Adaptor protein 3BP2 positively regulates the high affinity IgE receptor (FcepsilonRI)-mediated activation of degranulation in mast cells. Genetic study identified the point mutations of 3BP2 gene in human-inherited disease cherubism. The multiple cysts in cherubism lesion of jaw bones are filled with the activated osteoclasts and stromal cells, including mast cells. By over-expression study using rat basophilic leukaemia RBL-2H3 mast cells, we have analysed the effect of the point mutations on the function of 3BP2 protein, which plays a positive regulatory role on FcepsilonRI-mediated mast cell activation. Over-expression of 3BP2 mutants suppressed the antigen-induced degranulation and cytokine gene transcription. Antigen-induced phosphorylation of Vav1, activation of Rac1, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen activated protein kinase (MAPK), inhibitor of nuclear factor kappaB kinase (IKK) and nuclear factor of activated T cells (NFAT) were all impaired in the cells over-expressing the cherubism mutants of 3BP2. Furthermore, cherubism mutations of 3BP2 may abrogate the binding ability to interact with chaperone protein 14-3-3. These results demonstrate that over-expression of the mutant form of 3BP2 inhibits the antigen-induced mast cell activation. It suggests that point mutations of 3BP2 gene cause the dysfunction of 3BP2 in vivo.
authors.affiliation: Division of Proteomics, Department of Genome Sciences, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: S M Shahjahan
authors.initials: SM
authors.lastname: Miah
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hatani
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Qu
authors.forename: Hirohei
authors.initials: H
authors.lastname: Yamamura
authors.forename: Kiyonao
authors.initials: K
authors.lastname: Sada
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002636:Cherubism / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D008407:Mast Cells / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D051381:Rats; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C109073:SH3BP2 protein, human; C496618:VAV1 protein, human; C496620:Vav1 protein, rat; D020928:Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein