The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta
The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta
复制标题
DOI：
10.1242/dev.01825
复制
发表时间：
2005-05-01
期刊：
影响因子：
4.6
通讯作者：
Rubin, GM
中科院分区：
文献类型：
--
作者：
Lai, EC;Roegiers, F;Rubin, GM
Delta/Serrate/LAG2 （DSL）家族的受体Notch及其配体是Notch通路的核心组成部分，Notch通路是调节动物发育过程中模式形成的基本细胞信号系统。果蝇和爪蟾Neuralized以及斑马鱼Mind bomb可以直接使Delta泛素化，这两种不相关的ring型E3泛素连接酶具有促进Delta内吞作用和信号活性的共同能力。虽然在大多数后生动物中都发现了神经化和思维炸弹的同源物，但它们在任何单一生物中对Notch信号的相对贡献尚未得到评估。我们在这里表明，果蝇的思维炸弹（D-mib）同源物是Notch信号的一个积极组成部分，这是多个神经化独立、Notch依赖的发育过程所必需的。此外，我们发现D-mib在物理和功能上与Serrate和Delta都有关联。我们发现D-mib利用其泛素连接酶活性来促进DSL配体活性，这种活性与其诱导Delta和Serrate的内吞和降解的能力相关（另见Le Borgne et al., 2005）。我们进一步证明D-mib可以在多种细胞命运决定中取代Neuralized，这些决定绝对需要内源性Neuralized，这证明了这两种不相关的泛素连接酶在调节Notch信号传导方面具有高度相似的活性。我们得出结论，神经化和D-mib对Delta和Serrate的泛素化是果蝇发育过程中DSL配体激活的必要特征。
The receptor Notch and its ligands of the Delta/Serrate/LAG2 (DSL) family are the central components in the Notch pathway, a fundamental cell signaling system that regulates pattern formation during animal development. Delta is directly ubiquitinated by Drosophila and Xenopus Neuralized, and by zebrafish Mind bomb, two unrelated RING-type E3 ubiquitin ligases with common abilities to promote Delta endocytosis and signaling activity. Although orthologs of both Neuralized and Mind bomb are found in most metazoan organisms, their relative contributions to Notch signaling in any single organism have not yet been assessed. We show here that a Drosophila ortholog of Mind bomb (D-mib) is a positive component of Notch signaling that is required for multiple Neuralized-independent, Notch-dependent developmental processes. Furthermore, we show that D-mib associates physically and functionally with both Serrate and Delta. We find that D-mib uses its ubiquitin ligase activity to promote DSL ligand activity, an activity that is correlated with its ability to induce the endocytosis and degradation of both Delta and Serrate (see also Le Borgne et al., 2005). We further demonstrate that D-mib can functionally replace Neuralized in multiple cell fate decisions that absolutely require endogenous Neuralized, a testament to the highly similar activities of these two unrelated ubiquitin ligases in regulating Notch signaling. We conclude that ubiquitination of Delta and Serrate by Neuralized and D-mib is an obligate feature of DSL ligand activation throughout Drosophila development.