Furin与其底物Notch-1相互作用与胰腺癌的发生

Interaction of Furin and its Substrates Notch-1 in the Development of Pancreatic Cancer

细胞内多种蛋白质前体比如细胞基质金属蛋白酶、生长因子、激素、受体等在成熟之前,必须经过Furin等蛋白转化酶对其进行剪切,才能发挥生物学功能.这些蛋白质中部分成员与肿瘤的发生、发展密切相关,因此Furin等蛋白转换酶活性及其对底物剪切的调控已成为肿瘤防治领域的研究靶点.研究表明Notch-1信号在胰腺癌细胞中处于高活化状态,与胰腺癌的发生及进展息息相关,阻断Notch-1激活可抑制胰腺癌细胞的生长.虽然,Furin对Notch-1的剪切是Notch-1活化的关键步骤,有关这一生物过程的调节,目前不甚清楚.几乎所有的实体瘤均存在非受体酪氨酸激酶c-Src的过度激活,它主要通过磷酸化修饰作用调节下游信号进而影响肿瘤细胞的生物学行为.猜测c-Src可能对Notch-1活化有重要的影响作用.从Notch-1信号通路、c-Src、高尔基体内Furin与Notch-1的相互作用等方面来阐述它们之间的关系.

Many protein precursors such as matrix metalloproteases, growth factors, hormones, and receptors have been identified the furin substrates. They must be cleaved before maturation and activated. Many of these members have vital roles in the progress of tumoregenesis. So, the association between Furin and its substrates should be regulated by some mechanisms. The abnormal activation of signaling molecules plays an important role in the development of tumor. Studies have shown that Notch-1 signaling is activated in Pan-creatic cancer and blocking Notch-1 activation can inhibit the growth of Pancreatic cancer cells. Although the cleavage of Notch-1 by Furin is necessary for Notch-1 activation, the mechanism governing Noteh-l-Fu-rin association was not clear. Studies have shown that the over-activation of tyrosine kinase c-Src exist in nearly all solid tumors. It regulates the downstream signaling by phosphorylation and thus affects the subse-quent biological behavior of tumor cells. It indicate that c-Src may play a crucial role in activating Notch-1. It will shed light on the relationship among Notch-1 signal pathway, c-Src, furin interaction with its substrates Notch-1 in Golgi.