title: Enhancement of B-cell receptor signaling by a point mutation of adaptor protein 3BP2 identified in human inherited disease cherubism.
abstract: Tyrosine phosphorylation of adaptor protein c-Abl-Src homology 3 (SH3) domain-binding protein-2 (3BP2, also referred to SH3BP2) positively regulates the B-cell antigen receptor (BCR)-mediated signal transduction, leading to the activation of nuclear factor of activated T cells (NFAT). Here we showed the effect of the proline to arginine substitution of 3BP2 in which is the most common mutation in patients with cherubism (P418R) on B-cell receptor signaling. Comparing to the wild type, overexpression of the mutant form of 3BP2 (3BP2-P416R, corresponding to P418R in human protein) enhanced BCR-mediated activation of NFAT. 3BP2-P416R increased the signaling complex formation with Syk, phospholipase C-γ2 (PLC-γ2), and Vav1. In contrast, 3BP2-P416R could not change the association with the negative regulator 14-3-3. Loss of the association mutant that was incapable to associate with 14-3-3 could not mimic BCR-mediated NFAT activation in Syk-deficient cells. Moreover, BCR-mediated phosphorylation of extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was not affected by P416R mutation. These results showed that P416R mutation of 3BP2 causes the gain of function in B cells by increasing the interaction with specific signaling molecules.
authors.affiliation: Division of Microbiology, Department of Pathological Sciences, University of Fukui, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogi
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakashima
authors.forename: Kazuyasu
authors.initials: K
authors.lastname: Chihara
authors.forename: Kenji
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Horiguchi
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Fujieda
authors.forename: Kiyonao
authors.initials: K
authors.lastname: Sada
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D019556:COS Cells; D002460:Cell Line; D002636:Cherubism / Q000235:genetics* / Q000378:metabolism*; D002522:Chlorocebus aethiops; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics; D010766:Phosphorylation; D017354:Point Mutation / Q000235:genetics*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D015533:Transcriptional Activation; D014443:Tyrosine / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D050778:NFATC Transcription Factors; D011947:Receptors, Antigen, B-Cell; C109073:SH3BP2 protein, human; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4