ダイメリゼーションに依存するメカニズムは,RAFの触媒活性化を駆動する
Thanashan Rajakulendran1, Malha Sahmi, Martin Lefrançois
1Centre for Systems Biology, Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada.
Nature
|September 4, 2009
まとめ
RAFキナーゼは,サイド・トゥ・サイド・ダイメリゼーションを通じて活性化され,KSRを含むプロセスであり,BRAFが誘発するがんにとって決定的なものです. このダイマーインターフェースをターゲットにすることで,腫瘍発生に対する潜在的な治療戦略が提供されます.
科学分野:
- 細胞の信号伝達経路は,
- 分子生物学は分子生物学である.
- がん研究 がん研究
背景:
- 細胞外信号調節キナーゼ (ERK) 経路は,細胞の成長,分化,生存を調節する.
- ERK経路の調節不良,特にBRAFのようなRAFキナーゼの変異によって,多くのヒトの癌に関与しています.
- RAFキナーゼの活性化メカニズムを理解することは,標的がん治療の開発に不可欠です.
研究 の 目的:
- RAFキナーゼ活性化の分子メカニズムを解明する.
- 経路調節におけるRAF二分化の役割を調査する.
- BRAF変異がんの潜在的な治療標的を特定する.
主な方法:
- 実験分析のためにドロソフィラ・シュナイダーS2細胞を使用した.
- 調査されたRAFキナーゼドメインの二分化.
- RAFとKSR (Rasのキナーゼ抑制剤) の相互作用を調べました.
主要な成果:
- RAFの触媒機能は,そのキナーゼ領域の特定のサイド・ツー・サイド・ダイマー形成によって調節されることを実証した.
- KSRがRAFとヘテロダイマーを形成し,RAFの活性化を誘発することを示した.
- RAFのサイド・ツー・サイド・ダイマー形成が腫瘍性BRAFシグナル伝達に不可欠であることを確認し,このダイメリゼーションを促進する変異を特定しました.
結論:
- RAFの活性化は,そのキナーゼ領域のサイド・ツー・サイド・ダイメリゼーションによって制御されます.
- KSRは,ヘテロディメリゼーションを通じてRAFの活性化の重要なレギュレータとして作用します.
- RAFのサイド・ツー・サイド・ダイマー・インターフェースは,BRAFに依存した癌の治療対象として有望な治療目標です.
さらに関連する動画
07:49Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
06:44Bioluminescence Resonance Energy Transfer (BRET)-Based Assay for Measuring Interactions of CRAF with 14-3-3 Proteins in Live Cells
Published on: March 1, 2024
関連する概念動画
01:14Rab Proteins
Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
02:38The Ras Gene
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Ras is a superfamily...
01:19Interactions Between Signaling Pathways
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
01:26Receptor Tyrosine Kinases
Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
01:24Small GTPases - Ras and Rho
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
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...