| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
Cbl-family proteins negatively regulate signaling through activated tyrosine kinases by acting as ubiquitin ligases. We elucidated roles of Cbl-family in the nervous system mainly by analyzing mice lacking the family members. We carried out histological analyses on Cbl- and Cbl-b- single knockout mice. In addition, we performed behavioral analyses on Cbl-b knockout mice that were highly backcrossed with C57BL/6 mice. Furthermore, we established Cre-mediated conditional Cbl/Cbl-b double knockout mice in which Cre was expressed in olfactory bulb and cerebral cortex. In these mice, the profile of tyrosine-phosphorylated proteins in the brain was different compared with that in wild-type, and Cbl- or Cbl-b-single knockout mice. The result suggest that Cbl and Cbl-b have overlapping roles in the brain. Establishment of other lines of conditional Cbl/Cbl-b double knockout mice is in progress by using different Cre-transgenic mice. We also searched for substrates for Cbl-family proteins in the brain. We found that mDab1, which is crucial for laminar formation, is ubiquitinated by Cbl upon being tyrosine-phosphorylated. Accordingly, tyrosine-phosphorylated mDab1 was degraded via proteasomes. Furthermore, we found that Cbl and Cbl-b suppressed signaling through TrkA, TrkB, Alk, and ErbB-4. Especially, we showed ubiquitination of Alk and ErbB-4 by Cbl, and identified tyrosine residues on these two kinases that were critical for Cbl-mediated ubiquitination.
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