Irreversible tyrosine kinase inhibitors induce the endocytosis and downregulation of ErbB2.

不可逆酪氨酸激酶抑制剂诱导 ErbB2 的内吞和下调。

• 发表时间: Jul 2023
• 来源期刊: Biochem Biophys Rep
• DOI: 10.1016/j.bbrep.2023.101436
• PMID: 36824069
• 文章类型: Journal Article
• 作者列表: Ghosh C,Xing Y,Cai J,Sun Y

关键词: Clathrin; Dynamin; ERK1/2, Extracellular signal-regulated kinase 1/2; Endocytosis; Endosome; ErbB2; ErbB2, Erb-b2 receptor tyrosine kinase 2; HNSCC, Head and neck squamous cell carcinoma; LAMP1, Lysosomal Associated Membrane Protein 1; RTK, Receptor tyrosine kinase; TKI, Tyrosine kinase inhibitor; Tyrosine kinase inhibitors

Abstract

Erb-b2 receptor tyrosine kinase 2 (ErbB2) is an oncogene that frequently overexpressed in a subset of cancers. Anti-ErbB2 therapies have been developed to treat these types of cancers. However, less is known about how anti-ErbB2 drugs affect the trafficking and degradation of ErbB2. We demonstrate that the reversible and irreversible tyrosine kinase inhibitors (TKIs) differentially modulate the subcellular trafficking and downregulation of ErbB2. Only the irreversible TKIs can induce the loss of ErbB2 expression, which is not dependent on proteasome or lysosome. The irreversible TKIs promote ErbB2 endocytosis from plasma membrane and enhance the ErbB2 accumulation at endosomes. The endocytosis of ErbB2 is mediated by a dynamin-dependent but clathrin-independent mechanism. Blocking of ErbB2 endocytosis can impair the TKI-induced ErbB2 downregulation.

摘要

Erb-b2受体酪氨酸激酶2（ErbB2）是一种癌基因，经常在癌症亚组中过度表达。已经开发了抗ErbB2疗法来治疗这些类型的癌症。然而,关于抗ErbB2药物如何影响ErbB2的运输和降解知之甚少。我们证明了可逆和不可逆的酪氨酸激酶抑制剂（TKIs）差异调节ErbB2的亚细胞运输和下调。只有不可逆的TKIs才能诱导ErbB2表达的丧失，不依赖于蛋白酶体或溶酶体。不可逆的TKIs促进ErbB2从质膜的内吞作用并增强ErbB2在内体的积累。ErbB2的内吞作用是由动力蛋白依赖性但不依赖于网格蛋白的机制介导的。ErbB2内吞作用的阻断可损害TKI诱导的ErbB2下调。