| Project/Area Number |
09044343
|
|---|
| Research Category |
Grant-in-Aid for international Scientific Research
|
| Allocation Type | Single-year Grants |
|---|
| Section | Joint Research |
|---|
| Research Field |
Immunology
|
|---|
| Research Institution | Kansai Medical University |
|---|
Principal Investigator |
KUROSAKI Tomohiro Kansai Medical University, Department of Medicine, Professor, 医学部, 教授 (50178125)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
RAVETCH Jeffrey V The Rockefeller University, Laboratory of Molecular Genetics and Immunology, Pro, 分子免疫学部門, 教授
RAVETCH jeff ロクフェラー大学, 分子免疫学部門, 教授
|
|---|
| Project Period (FY) |
1997 – 1998
|
| Project Status |
Completed (Fiscal Year 1998)
|
| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1998: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1997: ¥2,100,000 (Direct Cost: ¥2,100,000)
|
|---|
| Keywords | BCR signaling / FcgammaRIIB / ITIM / SHIP / Btk / 抑制性レセプター / FcyRIIB / FcγRIIB |
|---|
| Research Abstract |
The ability of B cells to respond to antigen relies on signals transmitted through the B cell antigen receptor (BCR) complex. Activation of cytoplamic protein tyrosine kinases (PTKs) is the earliest measurable biochemical response to BCR cross-linking. This initial event leads to the generation of secondary signals including Ras activation, phosphatidylinositol 3-kinase (P1-3K) activation, turnover of phosphoinositides. and calcium mobilization, Both the strength and duration of the BCR-elicited signal are important in directing biological responses of B cells such as proliferation, differentiation. and apoptosis. Thus, attenuation and termination of these activation signals are also critical components for B cell response.
B cell activation is inhibited by crosslinking FcgammaRIIB with the BCR, The cytoplasmic domain of FcgammaRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM), which is necessary for the inhibitory function of the receptor. Phosphorylation of the tyrosine in the ITIM by the activated PTK(s) is critical to its inhibitory mechanism. Although the phosphorylated FcgammaRIIB ITIM associates with the SH2-containing protein tyrosine phosphatase SHP-1 and the SH2-containing inositol polyphosphate 5'-phosphatase SHIP, our data have shown that inhibition by FcgammaRIIB involves primarily SHIP.
Membrane recruitment of SHIP was responsible for the inhibitory signal generated by FcgammaRIIB coligation to the BCR.By reducing the level of PIP3. SHIP regulated the association of the Btk with the mebrane through PH domain-phospholinositol lipid interactions. Inhibition of BCR signaling by FcyRIIB coligation was suppressed by the expression of Btk as a membrane-associated chimera. Thus, our results suggest that recruited SHIP by FcgammaRIIB reduces the level of PIP3, leading to Btk downregulation and thereby calcium fluxes.
|
