Nectin-4 cis-interacts with ErbB2 and its trastuzumab-resistant splice variants, enhancing their activation and DNA synthesis
Nectin-4 cis-interacts with ErbB2 and its trastuzumab-resistant splice variants, enhancing their activation and DNA synthesis
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DOI：
10.1038/s41598-019-55460-9
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发表时间：
2019-12-12
影响因子：
4.6
通讯作者：
Takai, Yoshimi
中科院分区：
文献类型：
--
作者：
Kedashiro, Shin;Sugiura, Ayumu;Takai, Yoshimi
Nectin-4细胞粘附分子和ErbB 2酪氨酸激酶受体在包括乳腺癌在内的许多癌症中上调，并促进癌细胞增殖和转移。使用人乳腺癌细胞系T47 D和SUM 190-PT，其中nectin-4和ErbB 2都上调，我们在这里显示，nectin-4顺式相互作用与ErB 2和增强其二聚化和激活，随后激活磷酸肌醇3-激酶-AKT信号通路的DNA合成。nectin-4的第三个免疫球蛋白样结构域与ErbB 2的结构域IV顺式相互作用。该区域不同于曲妥珠单抗相互作用区域，但包含在ErbB 2、p95-ErbB 2和ErbB 2 Delta Ex 16的曲妥珠单抗抗性剪接变体中。Nectin-4也与这些曲妥珠单抗抗性剪接变体顺式相互作用，并增强了DNA合成的磷酸肌醇3-激酶-AKT信号通路的激活。此外，nectin-4增强p95-ErbB 2诱导的JAK-STAT 3信号通路的激活，但不增强ErbB 2或ErbB 2 Delta Ex 16诱导的JAK-STAT 3信号通路的激活。这些结果表明，nectin-4顺式相互作用与ErbB 2及其曲妥珠单抗耐药剪接变异体，并增强这些受体和下游信号转导通路的激活在一个新的机制。
Nectin-4 cell adhesion molecule and ErbB2 tyrosine kinase receptor are upregulated in many cancers, including breast cancer, and promote cancer cell proliferation and metastasis. Using human breast cancer cell lines T47D and SUM190-PT, in which both nectin-4 and ErbB2 were upregulated, we showed here that nectin-4 cis-interacted with ErB2 and enhanced its dimerization and activation, followed by the activation of the phosphoinositide 3-kinase-AKT signalling pathway for DNA synthesis. The third immunoglobulin-like domain of nectin-4 cis-interacted with domain IV of ErbB2. This region differs from the trastuzumab-interacting region but is included in the trastuzumab-resistant splice variants of ErbB2, p95-ErbB2 and ErbB2 Delta Ex16. Nectin-4 also cis-interacted with these trastuzumab-resistant splice variants and enhanced the activation of the phosphoinositide 3-kinase-AKT signalling pathway for DNA synthesis. In addition, nectin-4 enhanced the activation of the p95-ErbB2-induced JAK-STAT3 signalling pathway, but not the ErbB2- or ErbB2 Delta Ex16-induced JAK-STAT3 signalling pathway. These results indicate that nectin-4 cis-interacts with ErbB2 and its trastuzumab-resistant splice variants and enhances the activation of these receptors and downstream signalling pathways in a novel mechanism.