Mammalian NOTCH-1 activates β1 integrins via the small GTPase R-Ras
Mammalian NOTCH-1 activates β1 integrins via the small GTPase R-Ras
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DOI：
10.1074/jbc.m703601200
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发表时间：
2007-09-28
影响因子：
4.8
通讯作者：
Sethi, Tariq
中科院分区：
文献类型：
--
作者：
Hodkinson, Philip S.;Elliott, Paul. A.;Sethi, Tariq
Notch是重要细胞命运决定的中央调节器。Notch激活产生不同的细胞效应，表明存在依赖于上下文的控制机制。遗传学研究表明，Notch和整合素突变在关键发育过程中具有相关的表型，如血管发育和体节发生。我们发现，哺乳动物Notch-1的细胞内结构域激活整合素，而不影响整合素的表达。整合素活化依赖于γ-分泌酶介导的膜结合Notch的膜内切割，释放激活R-Ras的细胞内Notch，而不依赖于CSL转录。Notch还逆转H-Ras和Raf-mediated整合素抑制而不影响ERK磷酸化。无效切割的膜结合Notch突变体或缺乏锚蛋白重复序列的细胞内Notch突变体不激活R-Ras或整联蛋白。Msx 2相互作用核靶（MINT）蛋白与Notch的共表达或缺乏C-末端反式激活/PEST结构域的细胞内Notch-1截短突变体的表达抑制Notch转录活性而不影响整联蛋白激活。Notch配体，Delta样配体-4，刺激R-Ras依赖性α 5 β 1整联蛋白介导的粘附，证明了该途径的生理相关性。这种新的非CSL依赖性Notch/R-Ras通路提供了一种分子机制来解释多细胞生物体发育过程中Notch、整合素和Ras的相互作用。
Notch is a central regulator of important cell fate decisions. Notch activation produces diverse cellular effects suggesting the presence of context-dependent control mechanisms. Genetic studies have demonstrated that Notch and integrin mutations have related phenotypes in key developmental processes such as vascular development and somitogenesis. We show that the intracellular domain of mammalian Notch-1 activates integrins without affecting integrin expression. Integrin activation is dependent on gamma-secretase-mediated intramembranous cleavage of membrane-bound Notch releasing intracellular Notch that activates R-Ras, independent of CSL-transcription. Notch also reverses H-Ras and Raf-mediated integrin suppression without affecting ERK phosphorylation. Membrane-bound Notch mutants that are inefficiently cleaved or intracellular Notch mutants lacking the ankyrin repeat sequence do not activate R-Ras or integrins. Co-expression of Msx2-interacting nuclear target ( MINT) protein with Notch or expression of intracellular Notch-1 truncation mutants lacking the C-terminal transactivation/PEST domain suppresses Notch transcriptional activity without affecting integrin activation. Notch ligand, Delta-like ligand-4, stimulates R-Ras-dependent alpha 5 beta 1 integrin-mediated adhesion, demonstrating the physiological relevance of this pathway. This new CSL-independent Notch/R-Ras pathway provides a molecular mechanism to explain Notch, integrin, and Ras cross-talk during the development of multicellular organisms.