EGFR信号转导机制及靶向治疗

综述了EGFR基本结构特征及其介导细胞信号转导的机制，论述了基于EGFR靶向治疗的机理及研究现状。指出，EGFR是最早被发现并研究的RTK家族成员，其蛋白结构分成胞外域、跨膜区与胞内域三部分。EGFR介导细胞信号转导的核心机制是配体EGF与EGFR胞外域结合，通过变构作用与二聚化作用，使胞内域通过反式激活完成对受体末端酪氨酸残基的磷酸化，进而招募下游信号因子完成细胞信号转导过程。质膜结构与组成、EGFR跨膜区的组成及胞外域的有无、EGFR的内吞及泛素依赖性降解过程都调控EGFR细胞信号转导过程。阻断EGFR信号通路可抑制表皮肿瘤细胞成长。EGFR已经成为表皮肿瘤治疗的重要靶点。

EGFR Signal Transduction Mechanism and Targeted Therapy

The mechanisms of EGFR signal transduction and targeted therapy are reviewed. Epidermal growth factor receptor （EGFR） belongs to the ErbB family （receptor protein tyrosine kinase, RTK）, which insert into the cell membrane with its transmembrane domain. EGFR recognizes the ligands and regulates the intracellular tyrosine kinase activity through the extracellular domain （ECD）, which called tethered model. The C - lobe interacts with N - lobe in another EGFR TK domain , forms an asymmetric dimer and activates the follow EGFR molecule to catalyze and transfer the γ- phosphate group of ATP to tyrosine residues in CT. These tyrosine residues phosphorylated by transphosphorylation of the EGFR dimer are crucial for recruitment and activation of secondary messengers. These secondary signaling proteins contain SH2 and PTB domain which associate with CT region and intrinsic enzymatic activities which interact with other proteins, phospholipids or nucleic acids. The active EGFR induces ubiquitination, endocytosis and subsequent degradation. The cell membrane plays an important role in EGFR signaling pathway, its composition and structure regulate the activities of EGFR. EGFR is over - expressed in lots of solid tumors, and targeting EGFR as an option has led to the development of several anti - EGFR strategies for cancer treatment.