Frankfurt Institute for Molecular Life Sciences (FMLS) and Institute of Biochemistry II, Johann Wolfgang Goethe University School of Medicine, Frankfurt am Main, Germany.
Molecular Signal Transduction, Institute of Neurology (Edinger Institute), Johann Wolfgang Goethe University School of Medicine, Frankfurt am Main, Germany.
Bioessays. 2010 Jun;32(6):481-487. doi: 10.1002/bies.200900140.
Soluble components of Notch signalling can be applied to manipulate a central pathway essential for the development of metazoans and often deregulated in illnesses such as stroke, cancer or cardiovascular diseases. Commonly, the Notch cascade is inhibited by small compound inhibitors, which either block the proteolysis of Notch receptors by gamma-secretases or interfere with the transcriptional activity of the Notch intracellular domain. Specific antibodies can also be used to inhibit ligand-induced activation of Notch receptors. Alternatively, naturally occurring endogenous inhibitors of Notch signalling might offer a specific way to block receptor activation. Examples are the soluble variants of the canonical Notch ligand Jagged1 and the non-canonical Notch ligand Dlk1, both deprived of their transmembrane regions upon ectodomain shedding, or the bona fide secreted molecule EGFL7. We present frequently used methods to decrease Notch signalling, and we discuss how soluble Notch inhibitors may be used to treat diseases.
Notch 信号的可溶性成分可用于操纵对后生动物的发育至关重要的中央通路，并且经常在中风、癌症或心血管疾病等疾病中失调。通常，Notch 级联反应被小分子化合物抑制剂抑制，这些抑制剂要么阻止γ-分泌酶对 Notch 受体的蛋白水解，要么干扰 Notch 细胞内结构域的转录活性。特异性抗体也可用于抑制配体诱导的 Notch 受体激活。或者，Notch 信号的天然内源性抑制剂可能提供一种特异性阻断受体激活的方法。例如，经典 Notch 配体 Jagged1 的可溶性变体和非经典 Notch 配体 Dlk1，它们在胞外结构域脱落时都失去了跨膜区域，或者是真正的分泌分子 EGFL7。我们介绍了常用于降低 Notch 信号的方法，并讨论了可溶性 Notch 抑制剂如何用于治疗疾病。
