2019 Fiscal Year Final Research Report
Elucidation of pathogenesis of Noonan syndrome by novel causative gene LZTR1
| Project/Area Number |
18K15657
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Tohoku University |
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Principal Investigator |
Abe Taiki 東北大学, 医学系研究科, 助教 (40810594)
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Keywords | RASopathies / Noonan症候群 / ユビキチン・プロテアソーム経路 / LZTR1 / RAS/MAPK |
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| Outline of Final Research Achievements |
Leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a member of the BTB-Kelch superfamily, which interacts with the Cullin3 (CUL3)-based E3 ubiquitin ligase complex. LZTR1 is a causative gene of RASopathies, which are caused by germline mutations in genes encoding various components of the RAS/MAPK signaling pathway. However, no evidence regarding the functional interaction between LZTR1 and the RAS/MAPK signaling pathway had been reported.
In this study, we revealed that (1) LZTR1 regulates RAS/MAPK signal activity through the interaction of RAS and PPP1CB/SHOC2 /cRAF-complex, and (2) LZTR1 is involved in RAS degradation via the ubiquitin-proteasome pathway.
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| Free Research Field |
分子生物学
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| Academic Significance and Societal Importance of the Research Achievements |
LZTR１はRASopahitesの原因分子であるとされていたもののRAS/MAPKシグナル伝達経路との関係は不明であった。そのため、治療法や治療薬の開発に際して治療標的分子を絞り込むことができず、各症状に対する対症療法以外に手立てがなかった。加えて、RASopathiesに分類される疾患は希少疾患であるためがんなどの大衆疾患に比べて研究開発が遅れている領域である。今回、LZTR1とRAS/MAPKシグナル伝達経路との関係が解明されたことで、治療薬開発における標的分子が明確となり、将来的な治療薬の開発が大いに期待される。
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