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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity
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Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity

机译：Ab诱导的胞外域脱落介导肝细胞生长因子受体下调并阻碍生物学活性

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摘要

Targeting tyrosine kinase receptors (RTKs) with specific Abs is a promising therapeutic approach for cancer treatment, although the molecular mechanism(s) responsible for the Abs' biological activity are not completely known. We targeted the transmembrane RTK for hepatocyte growth factor (HGF) with a monoclonal Ab (DN30). In vitro, chronic treatment of carcinoma cell lines resulted in impairment of FGF-induced signal transduction, anchorage-independent growth, and invasiveness. In vivo, administration of DN30 inhibited growth and metastatic spread to the lung of neoplastic cells s.c. transplanted into immunodeficient nuu mice. This Ab efficiently down-regulates HGF receptor through a molecular mechanism involving a double proteolytic cleavage: (i) cleavage of the extracellular portion, resulting in "shedding" of the ectodomain, and (ii) cleavage of the intracellular domain, which is rapidly degraded by the proteasome. Interestingly, the "decoy effect" generated by the shed ectodomain, acting as a dominant negative molecule, enhanced the inhibitory effect of the Ab.
机译：用酪氨酸激酶受体（RTKs）靶向特定的Abs是一种有前途的癌症治疗方法，尽管导致Abs生物活性的分子机制尚不完全清楚。我们针对跨膜RTK的单克隆抗体（DN30）肝细胞生长因子（HGF）。在体外，癌细胞系的慢性治疗导致FGF诱导的信号转导，锚定非依赖性生长和侵袭性受损。在体内，DN30的施用抑制了肿瘤细胞皮下的生长和向肺的转移扩散。移植到免疫缺陷的nu / nu小鼠中。该抗体通过涉及双重蛋白水解切割的分子机理有效地下调HGF受体：（i）细胞外部分的切割，导致胞外域的“脱落”，和（ii）细胞内结构域的切割，其迅速降解。通过蛋白酶体。有趣的是，由脱落的胞外域产生的“诱饵作用”，作为主要的负分子，增强了抗体的抑制作用。

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