EGFR and ErbB2 are functionally coupled to CD44 and regulate shedding, internalization and motogenic effect of CD44
EGFR and ErbB2 are functionally coupled to CD44 and regulate shedding, internalization and motogenic effect of CD44
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DOI：
10.1016/j.canlet.2008.01.014
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发表时间：
2008-05-18
期刊：
影响因子：
9.7
通讯作者：
Nagy, Peter
中科院分区：
文献类型：
--
作者：
Palyi-Krekk, Zsuzsarma;Barok, Mark;Nagy, Peter
ErbB受体酪氨酸激酶家族的激活与一系列人类癌症有关。ErbB蛋白介导的跨膜信号被多肽生长因子刺激，并被曲妥珠单抗和pertuzumab等单抗阻断。ErbB受体与非ErbB蛋白如CD44共同发挥作用。在这里，我们发现，表皮生长因子(EGF)和Hereglin诱导对曲妥珠单抗耐药的ErbB2过表达的细胞株JIMT-1中CD44脱落，伴随着CD44的内化和膜内蛋白分解，以及细胞运动性的增强。EGF和hereglin的这些作用可被pertuzumab阻断。曲妥珠单抗可抑制谷氨酸寡糖和透明质酸低聚糖诱导的CD44的脱落和内化及其成骨作用。曲妥珠单抗还可以阻断体内JIMT-1移植瘤中CD44的脱落。同时，透明质酸低聚糖体外处理可提高曲妥珠单抗的内化率。我们的实验指出了一种意想不到的，但可能是重要的作用机制，即ErbB受体靶向的单抗用于癌症的治疗。(C)2008爱思唯尔爱尔兰有限公司。保留所有权利。
Activation of the ErbB family of receptor tyrosine kinases is involved in a range of human cancers. Transmembrane signaling mediated by ErbB proteins is stimulated by peptide growth factors and is blocked by monoclonal antibodies such as trastuzumab and pertuzumab. ErbB receptors exert their function in conjunction with non-ErbB proteins, e.g. CD44. Here we show that epidermal growth factor (EGF) and heregulin induce CD44 shedding in JIMT-1, an ErbB2-overexpressing cell line resistant to trastuzumab, accompanied by internalization and intramembrane proteolysis of CD44 and enhanced cellular motility. These effects of EGF and heregulin are blocked by pertuzumab. Trastuzumab inhibits the heregulin- and hyaluronan oligosaccharide-induced shedding and internalization of CD44 and their motogenic effect. Trastuzumab also blocks CD44 shedding from JIMT-1 xenograft tumors in vivo. At the same time the internalization rate of trastuzumab is increased by hyaluronan oligosaccharide treatment in vitro. Our experiments point to an unexpected, but potentially important mechanism of action of ErbB receptor-targeted monoclonal antibodies used in the treatment of cancer. (C) 2008 Elsevier Ireland Ltd. All rights reserved.