NOTCH3
小结
NOTCH3编码蛋白是一种跨膜受体，参与进化保守的细胞-细胞信号转导途径。NOTCH3受体与相邻细胞中配体分子的相互作用导致γ分泌酶对NOTCH3蛋白酶切水解。酶切后的胞内NOTCH3结构域可以激活细胞核中的基因表达，并调节细胞分化、生长、增殖、存活和代谢的各个方面。NOTCH3在信号传导中的特定作用根据细胞环境而变化。NOTCH3基因突变起初在伴皮质下梗死常染色体显性遗传性脑动脉病和脑白质病（CADASIL）中得到鉴定。在T细胞急性淋巴细胞白血病（T-ALL）和三阴性乳腺癌中已经鉴定出NOTCH3的激活突变和局部扩增。NOTCH3失活突变是最常见的实体瘤，即鳞状细胞癌。
NOTCH3 is a transmembrane receptor that participates in an evolutionarily conserved cell-to-cell signal transduction pathway. Interaction of the NOTCH3 receptor with ligand molecules on adjacent cells results in the proteolytic cleavage of NOTCH3 by gamma-secretase. The cleaved intracellular NOTCH3 domain can then activate gene expression in the nucleus and regulate various aspects of cell differentiation, growth, proliferation, survival, and metabolism. The specific effects of NOTCH3 signaling vary depending on the cellular context. NOTCH3 mutations were initially identified in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Activating mutations and focal amplifications of NOTCH3 have been identified in T-cell acute lymphoblastic leukemia (T-ALL), and triple negative breast cancer. These NOTCH3 activating mutations either enhance the cleavage of NOTCH3 by gamma-secretase or extend the half-life of intracellular NOTCH3. NOTCH3 inactivating mutations are most common in solid tumors, namely squamous cell carcinomas, and occur as missense, frameshift or nonsense mutations in important NOTCH3 functional domains.