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.
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Authors | Kazuhiro Ogi, Kenji Nakashima, Kazuyasu Chihara, Kenji Takeuchi, Tomoko Horiguchi, Shigeharu Fujieda, Kiyonao Sada |
Journal | Genes to cells : devoted to molecular & cellular mechanisms
(Genes Cells)
Vol. 16
Issue 9
Pg. 951-60
(Sep 2011)
ISSN: 1365-2443 [Electronic] England |
PMID | 21794028
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2011 The Authors. Journal compilation © 2011 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd. |
Chemical References |
- 14-3-3 Proteins
- Adaptor Proteins, Signal Transducing
- Intracellular Signaling Peptides and Proteins
- Multiprotein Complexes
- NFATC Transcription Factors
- Receptors, Antigen, B-Cell
- SH3BP2 protein, human
- Tyrosine
- Protein-Tyrosine Kinases
- SYK protein, human
- Syk Kinase
- Extracellular Signal-Regulated MAP Kinases
- MAP Kinase Kinase 4
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Topics |
- 14-3-3 Proteins
(metabolism)
- Adaptor Proteins, Signal Transducing
(genetics)
- Animals
- B-Lymphocytes
(metabolism)
- COS Cells
- Cell Line
- Cherubism
(genetics, metabolism)
- Chlorocebus aethiops
- Extracellular Signal-Regulated MAP Kinases
(metabolism)
- Humans
- Intracellular Signaling Peptides and Proteins
(metabolism)
- MAP Kinase Kinase 4
(metabolism)
- Multiprotein Complexes
(metabolism)
- NFATC Transcription Factors
(genetics)
- Phosphorylation
- Point Mutation
(genetics)
- Protein Binding
- Protein-Tyrosine Kinases
(metabolism)
- Receptors, Antigen, B-Cell
(metabolism)
- Signal Transduction
- Syk Kinase
- Transcriptional Activation
- Tyrosine
(metabolism)
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