| Project/Area Number |
10557038
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Immunology
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| Research Institution | Kurume University |
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Principal Investigator |
YOSHIMURA Akihiko Institute of Life Science, Kurume University, Professor, 分子生命科学研究所, 教授 (90182815)
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| Co-Investigator(Kenkyū-buntansha) |
YASUKAWA Hideo Institute of Life Science, Kurume University, Assistant Professor, 分子生命科学研究所, 助手 (60289361)
OHTSUBO Motoaki Institute of Life Science, Kurume University, Assistant Professor, 分子生命科学研究所, 助手 (10211799)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥12,300,000 (Direct Cost: ¥12,300,000)
Fiscal Year 1999: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 1998: ¥8,400,000 (Direct Cost: ¥8,400,000)
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| Keywords | tyrosine kinase / JAK / STAT / CIS / cytokine / knockout mice / tyrosine phosphorylation / interferon / SH2ドメイン / シグナル伝達 / APS |
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| Research Abstract |
To identify the novel substrate of tyrosine kinases which is important for proliferation or differentiation, we developed a two-hybrid screening using active c-kit as bait. We cloned new adaptor molecules, APS and STAP-1 which contain SH2 domain and PH domain. RT-POR analysis revealed that STAP-1 expression is restricted in bone marrow cell fraction expressing c-kit, and the highest expression was observed in CD34-Sca-1+c-Kit+Lin- hematopoietic stem cell enriched fraction. Murine myeloid cell line, M1 expressed high level of STAP-1. However, the expression was strongly repressed in response to leukemia inhibitory factor which induced monocytic differentiation of M1 cells, suggesting that STAP-1 is associated with undifferentiated cell type. In 293 cells, STAP-1 was tyrosine phosphorylated by activated c-kit. In vitro binding assay suggested that STAP-1 SH2 domain interacted with several tyrosine phosphorylated protein including c-kit and STAT5. These suggest that STAP-1 function as a a
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daptor molecule downstream of c-kit in hematopoietic stem cells.
Furthermore, we recently cloned a novel substrate of c-kit or other tyrosine kinases. This gene, we call WARS, does not contain any SH2 or PH domain but has a novel domain related to a gene that is a negative regulator of Ras-MAP kinase in Drosophila. We will try to find the function of this gene in development of cancer.
We cloned a novel SH2 protein JAB, that binds to the kinase domain of JAK2. JAB interacts with and inhibits JAK tyrosine kinases. Through the SH2 domain, JAB binds to a phosphotyrosine in the activation loop of the JAK kinases and suppresses their catalytic activity. We have shown that JAB is strongly induced by interferon-γ. We demonstrate that JAB deficient mice die perinatally with altered lymphoid development including the generation of activated T cells in vivo. The lethality is eliminated on a Rag2 or interferon-γ. Deficient background . Based on the results, we propose that JAB plays an essential role in negative feedback regulation of interferon-γ. Less
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