Tel2は,PI3Kに関連するタンパク質キナーゼの安定性を調節する
Hiroyuki Takai1, Richard C Wang, Kaori K Takai
1Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Cell
|December 28, 2007
まとめ
Tel2は,すべての哺乳類のフォスファディチルイノシトール3キナーゼ関連タンパク質キナーゼ (PIKKs) の安定性を維持するために不可欠です. この発見は,Tel2を明らかにしています.
科学分野:
- 細胞および分子生物学
- 遺伝学とゲノミクス
- バイオケミストリー バイオケミストリー
背景:
- Tel2は当初,テロメアの維持における役割のために酵母で特定されました.
- 哺乳類のTel2には明らかにテロメア機能がないが,胚の発達には不可欠である.
- Tel2は,チェックポイントキナーゼの活性化を含む,DNA損傷に対する細胞反応に影響します.
研究 の 目的:
- 哺乳類の細胞におけるTel2の機能を調査する.
- フォスファティジル・イノシトール3キナーゼ関連タンパク質キナーゼ (PIKKs) に対するTel2デリエーションの効果を決定する.
- Tel2がPIKKsを調節するメカニズムを解明する.
主な方法:
- マウスおよび胚性線維芽細胞における標的型遺伝子消去.
- 胚性線維芽細胞におけるTel2の条件付消去除.
- PIKKタンパク質レベル,mRNA発現,およびシグナル伝達経路の分析.
- In vivoパルスラベリングと共免疫プレシピテーションアッセイ.
主要な成果:
- Tel2の消去は胚の発達中に致命的であり,線維芽細胞のDNA損傷応答を損なう.
- Tel2の喪失は,ATM,ATR,DNA-PKcs,mTOR,SMG1およびTRRAPを含む6つの哺乳類PIKKのタンパク質レベルを大幅に低下させます.
- Tel2は,mRNAレベルではなく,ATMとmTORの安定性を制御しています.
- Tel2はATMとmTORに直接リンクしています.
結論:
- Tel2は,哺乳類におけるPIKKの安定性の重要な調節剤である.
- Tel2は,PIKKファミリーのタンパク質レベルを制御する保守的な役割を果たします.
- この発見は,Tel2が細胞シグナル伝達とDNA修復経路における重要な要因であることを強調しています.
関連する概念動画
02:54Protein Kinases and Phosphatases
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
02:54Protein Kinases and Phosphatases
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
01:20The JAK-STAT Signaling Pathway
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
01:22PI3K/mTOR/AKT Signaling Pathway
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a rapamycin-insensitive companion...