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Rac1のアクティベーションは,カノン的なWntシグナル伝達中にβ-カテニンの核の局所化を制御する
Ximei Wu1, Xiaolin Tu, Kyu Sang Joeng
1Department of Medicine, Washington University Medical School, St. Louis, MO 63110, USA.
Cell
|April 22, 2008
まとめ
Rac1の活性化は,Wnt信号伝達における核β-カテニンの蓄積に不可欠である. この経路は,JNK2キナーゼと特定のβ-カテニンのリン酸化部位を伴うもので,胚の肢体の発達に極めて重要です.
科学分野:
- 細胞生物学 細胞生物学
- 発達生物学 発達生物学について
- 分子シグナリング
背景:
- カノニカルWntシグナル伝達は,細胞の運命を決定し,発達と疾患の間に細胞の増殖に不可欠です.
- ベータ-カテニンの核の局所化は,正規のWnt信号伝達の重要なステップです.
- ベータ-カタニンの核への侵入を制御する正確なメカニズムは,まだ完全に理解されていません.
研究 の 目的:
- Wntシグナル伝達に対する反応としてβ-カテニンの核の局所化を制御するメカニズムを解明する.
- Wnt誘発のβ-カタニン核蓄積におけるRac1の役割を調査する.
- この経路を標的とした治療の可能性を探るため.
主な方法:
- Wnt誘発のβ-カテニンの核蓄積のためにRac1の活性化の必要性を調査した.
- セル191とセル605.5でβ-カテニンをリン酸化するJNK2キナーズの役割を調べました.
- マウスの胚性四肢の芽生えエクトドームでRac1の遺伝的アブレーションを活用した.
- Rac1,β-カタニン,およびDkk1.1の間の遺伝的相互作用を分析した.
主要な成果:
- Wnt刺激によるβ-カテニンの核蓄積は,Rac1の活性化を必要とする.
- Rac1の機能は,Ser191とSer605.5におけるβ-カテニンのJNK2媒介型リン酸化に依存しています.
- これらのリン酸化部位での変異は,Wnt誘発のβ-カタニンの核入りを阻害する.
- マウスの四肢芽のエクトダーマにおけるRac1の遺伝的消去は,Wntのシグナル伝達と四肢の発達を妨げます.
- Rac1は,四肢の増殖を制御するために,β-カテニンとDkk1との遺伝的相互作用を示しています.
結論:
- Rac1の活性化とそれに続くβ-カテニンのリン酸化は,正規のWnt信号伝達を制御する新しいメカニズムを表しています.
- この経路は,胚の肢体の発達に極めて重要です.
- 特定されたメカニズムは,Wnt経路に関連する疾患に対する潜在的な治療目標を提供します.
関連する概念動画
02:54Canonical Wnt Signaling Pathway
The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which results in tumor...
02:54Canonical Wnt Signaling Pathway
The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which results in tumor...
01:41Non-Canonical Wnt Signaling Pathways
Wnt is a zygotic effect gene that is expressed during very early embryonic development. It regulates various processes in animals starting from early development through the adult stage, such as organogenesis in the embryo and maintenance of neuronal and blood stem cells. Wnt proteins can induce a wide variety of intracellular pathways depending upon the specific abilities of different Wnt ligands to form a complex with shared and cognate receptors in the presence of different co-receptors. The...
01:41Non-Canonical Wnt Signaling Pathways
Wnt is a zygotic effect gene that is expressed during very early embryonic development. It regulates various processes in animals starting from early development through the adult stage, such as organogenesis in the embryo and maintenance of neuronal and blood stem cells. Wnt proteins can induce a wide variety of intracellular pathways depending upon the specific abilities of different Wnt ligands to form a complex with shared and cognate receptors in the presence of different co-receptors. The...
01:23Catenins
Catenins are characterized by multiple binding domains and dynamic structures that allow them to function as linker proteins in cell junction complexes. All catenins, except α-catenin, contain a characteristic protein sequence called the armadillo repeat and are therefore also called armadillo proteins.
Catenins in Cell Junctions
Catenins bind to cell adhesion molecules such as cadherins and link them to different cytoskeletal proteins depending on the type of cell junction. At the adherens...
Catenins in Cell Junctions
Catenins bind to cell adhesion molecules such as cadherins and link them to different cytoskeletal proteins depending on the type of cell junction. At the adherens...
01:07MAPK Signaling Cascades
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...