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: 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)
• 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

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)