Division of Microbiology, University of Fukui, Japan

Microbiology

Summary of Research Activities
Signal Transduction-Physiopathological role of the adaptor proteins in immune cells
Molecular scaffold, adaptor proteins have indispensable roles to switch the receptor-activating signals to the downstream effectors by assembling, targeting and regulating the signaling molecules. Several adaptor proteins are the substrate of proximal protein-tyrosine kinases. These molecules lack the catalytic activity, but they have multiple motifs and domains that allow binding to the other signaling molecules and therefore act as positive or negative regulators controlling the intracellular signal transduction. We are currently working on the signal transduction mediated by the adaptor protein 3BP2 (c-Abl Src homology 3 domain-binding protein-2, also referred to SH3BP2) to reveal its physiopathological role in lymphocytes and myeloid-lineage cells, by utilizing the techniques combine the various mutant cDNA transfection, RNA interference, and genetic analysis of the signaling molecules.

Adaptor protein 3BP2 is known to play a regulatory role in the immunoreceptor signaling. In mast cells, 3BP2 is rapidly tyrosine phosphorylated by the aggregation of the high affinity IgE receptor. Overexpression of 3BP2-SH2 domain results in the dramatic suppression of IgE-mediated tyrosine phosphorylation of PLC-g, Ca2+ mobilization and degranulation leading to the release of histamine. 3BP2 is a substrate of proximal protein-tyrosine kinase Syk. Phosphorylation of 3BP2-Tyr183 promotes the activation of Rac1 through the interaction with the SH2 domain of Vav1. Phosphorylation of 3BP2-Tyr446 induces the binding to the SH2 domain of upstream protein-tyrosine kinase Lyn and enhances its kinase activity. Thus, 3BP2 has a positive regulatory role in IgE-mediated mast cell activation.

In lymphocytes, the engagement of antigen receptor triggers tyrosine phosphorylation of 3BP2. Suppression of the 3BP2 expression by siRNA results in the inhibition of the antigen receptor-mediated activation of NFAT in T and B lymphocytes. Genetic analyses revealed that 3BP2 is required for the proliferation of B cells and B cell receptor signaling.

Point mutations of 3BP2 gene cause the rare human inherited disorder cherubism, characterized by excessive bone resorption in the jaw bones. These mutations cause substitution and deletion mutations of 3BP2. Cherubism is an autosomal dominant inherited disease characterized by multiple symmetrical cysts in mandible and maxilla, excessive bone degradation, and typical facial swelling. Genetic analysis identified the several substitution and deletion mutations in 3BP2 gene on chromosome 4p16.3. Deletion of 4p16.3 also correlates with Wolf-Hirschhorn syndrome and bladder cancer .

Signal Transduction by hepatitis C virus infection
Besides the study of immunoreceptor-mediated signal transduction, we have been interested in the signal transduction by the infection of hepatitis C virus (HCV). One of the non-structural proteins NS5A was found to be interacted with Syk, a potent tumor suppressor in breast cancer, and NS5A inhibits the kinase activity of Syk. This finding suggests the possible involvement of NS5A on the pathogenesis of hepatocellular carcinoma by chronic HCV infection.

We welcome you who are interested in life science, and who wish to clarify mysterious life phenomenon in a substantial level, especially by the analysis of signal transduction. Fur further information, please refer to our recent publications listed below.

Professor
Kiyonao Sada, MD, PhD.
E-mail: ksada@u-fukui.ac.jp
Address: Division of Microbiology,
Department of Pathological Sciences,
University of Fukui School of Medicine
23-3 Matsuoka-Shimoaizuki,
Eiheiji, Fukui 910-1193, Japan

Selected Publications

Tyrosine phosphorylation of 3BP2 regulates BCR-mediated activation of NFAT.
J. Biol. Chem. 284(49):33719-33728 (2009)
[Abstract]

Adaptor protein 3BP2 and cherubism.
Curr. Med. Chem. 15(6):549-554 (2008)
[Abstract]

A novel mitochondria ubiquitin ligase plays a critical role in mitochondrial dynamics.
EMBO J. 25(15):3618-3626 (2006)
[Abstract] [Full text]

Tyrosine phosphorylation of adaptor protein 3BP2 induces T cell receptor-mediated activation of transcription factor.
Biochemistry 44(10):3891-3898 (2005)
[Abstract] [Full text]

Negative regulation of FceRI-mediated mast cell activation by a ubiquitin-protein ligase Cbl-b.
Blood 103(5):1779-1786 (2004)
[Abstract] [Full text]

Activation of Syk protein-tyrosine kinase in response to osmotic stress requires the interaction with p21-activated protein kinase Pak2/g-PAK.
Mol. Cell. Biol. 24(1):71-83 (2004)
[Abstract] [Full text]