JAK-STATとMAPキナーゼをgp130経由で白血病抑制因子によって心筋細胞で活性化する
K Kunisada1, H Hirota, Y Fujio
1Department of Medicine III, Osaka University Medical School, Japan.
Circulation
|November 15, 1996
まとめ
白血病抑制因子 (LIF) は,心筋細胞におけるジャヌスキナーゼ信号トランスデューサーおよび転写活性化器 (JAK-STAT) とミトゲン活性化タンパク質キナーゼ (MAPK) 経路を活性化します. このgp130が媒介するシグナリングは,in vitroとin vivoの両方で急速に発生します.
科学分野:
- 心血管生物学 心血管生物学
- 細胞シグナル伝達 細胞信号伝達
- 分子医学は分子医学である.
背景:
- インターリューキン-6 (IL-6) に関連するサイトカインは,信号伝達のためにgp130を利用します.
- gp130の2つの主要な下流経路は,ジャヌスキナーゼ信号変換器と転写活性化器 (JAK-STAT) とラスミトゲン活性化タンパク質キナーゼ (MAPK) 経路である.
- これらの経路の心筋細胞における存在と活性化は,以前は特徴づけられていなかった.
研究 の 目的:
- 心臓筋細胞におけるgp130の下流にあるJAK-STATとMAPKの信号伝達経路の活性化を調査する.
- 心臓細胞におけるこれらの経路の活性化における白血病抑制因子 (LIF) の役割を決定する.
主な方法:
- 新生ラットの心筋細胞はLIFで刺激された.
- タンパク質の活性化は,イムノプレシピテーションとウエスタン・ブロッティングを用いて,フォスフォチロシンの活性化を評価した.
- 信号経路の阻害は,anti-gp130抗体を使用して研究されました.
- In vivo研究では,成人マウスの体内にLIFを静脈内注射し,その後心臓組織分析を行った.
主要な成果:
- LIF刺激により,心筋細胞におけるgp130,JAK1,STAT3のチロシンリン酸化が誘発された.
- ミトゲン活性化タンパク質キナーゼ (MAPK) は,LIF曝露の5分以内に最大活性化を示しました.
- アンチ-gp130抗体は,LIF誘発によるJAK1,STAT3,MAPKの活性化を阻害した.
- In vivoでは,LIF治療により,成人のマウスの心臓でgp130,STAT3,MAPKが活性化しました.
結論:
- 心筋細胞は,gp130.0.の下流にあるJAK-STATとMAPKの両方のシグナル伝達経路を持っています.
- LIFは,心筋筋細胞におけるこれらの経路を,インビトロとインビボの両方で迅速に活性化します.
- gp130の活性化は,心筋細胞内の新しいシグナル伝達メカニズムを表しています.
関連する概念動画
Interactions 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...
Amplifying Signals via Enzymatic Cascade
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
MAPK 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...
The 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...
TGF - β Signaling Pathway
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
Intracellular Signaling Affects Focal Adhesions
Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...
Some...


