Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain
Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain
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作者：
Schroeter, EH;Kisslinger, JA;Kopan, R
Notch蛋白是在整个发育过程中参与细胞命运选择的配体激活的跨膜受体（1-3）。Notch中不含已知的酶活性，并且其跨细胞膜转导信号的分子机制知之甚少。在许多情况下，Notch激活通过与DNA结合蛋白的CSL家族成员（其中CSL代表CBF 1、Su（H）、Lag-1）的结合导致细胞核中的转录变化（1-4）。由于Notch位于质膜中，CSL是一种核蛋白，因此提出了两种模型来解释它们如何相互作用（图I）。第一个结果表明，这两种物质在细胞膜上短暂地相互作用（1，5 -7）。第二种假设Notch被蛋白酶切割，使切割的片段进入GRAPHICS细胞核（6，8 -14）。在这里，我们表明，信号由一个组成型活性的膜结合的Notch-1蛋白需要的Notch inh非细胞结构域（NICD），它优先与CSL相互作用的蛋白水解释放。非常少量的NICD是活跃的，解释了为什么它是很难检测到在体内的核，我们还表明，它是配体结合，诱导释放NICD。
Notch proteins are ligand-activated transmembrane receptors involved in cell-fate selection throughout development(1-3). No known enzymatic activity is contained within Notch and the molecular mechanism by which it transduces signals across the cell membrane is poorly understood. In many instances, Notch activation results in transcriptional changes in the nucleus through an association with members of the CSL family of DNA-binding proteins (where CSL stands for CBF1, Su(H), Lag-1)(1-4). As Notch is located in the plasma membrane and CSL is a nuclear protein, two models have been proposed to explain how they interact (Fig. I). The first suggests that the two interact transiently at the membrane(1,5-7). The second postulates that Notch is cleaved by a protease, enabling the cleaved fragment to enter theGRAPHICSnucleus(6,8-14). Here we show that signalling by a constitutively active membrane-bound Notch-1 protein requires the proteolytic release of the Notch inh acellular domain (NICD), which interacts preferentially with CSL, Very small amounts of NICD are active, explaining why it is hard to detect in the nucleus in vivo, We also show that it is ligand binding that induces release of NICD.