EGFR 信号传导
中文名称
通路描述
表皮生长因子受体（EGFR）是 ERBB 家族膜结合糖蛋白酪氨酸激酶受体（RTK）的成员之一。EGFR 与其配体结合引起构象变化，暴露出 EGFR 细胞外域的二聚化界面，导致受体在细胞表面发生同源或异源二聚化。EGFR 细胞外域的二聚化触发细胞质 EGFR 区域的额外构象变化，使两个 EGFR 分子的激酶域达到催化活性构象。激活的 EGFR 二聚体在受体的细胞质尾部酪氨酸残基上发生自磷酸化。磷酸化的酪氨酸残基作为信号转导者和激活剂的内源底物招募的结合位点，这些信号转导者和激活剂随后刺激参与调节细胞增殖、分化和生存的细胞内信号转导级联反应。含有 GRB2 和 SOS1 的复合物直接招募到磷酸化的 EGFR 二聚体上，或者通过 SHC1 招募间接招募，促进 GDP 到 GTP 交换在 RAS 上，导致 RAF/MAP 激酶级联反应的激活。含有 GRB2 和 GAB1 的复合物结合到磷酸化的 EGFR 二聚体上导致形成活性 PI3K 复合物，将 PIP2 转化为 PIP3，并激活 AKT 信号传导。磷脂酶 C-gamma1（PLCG1）也可以通过 EGFR 磷酸酪氨酸残基作为 PLCG1 结合位点直接招募，导致 PLCG1 被 EGFR 磷酸化并激活 DAG 和 IP3 信号传导。CBL 泛素连接酶也可以下调 EGFR 信号传导。CBL 直接通过 EGFR C 尾部磷酸酪氨酸 Y1069（即成熟蛋白中的 Y1045）结合到磷酸化的 EGFR 二聚体上，并且经过 CBL 被 EGFR 磷酸化后，它变得活性并泛素化磷酸化的 EGFR 二聚体，将其靶向降解。EGFR 信号传导的直接关联辅助蛋白如 AAMP 和 FAM83B 的结合正在被研究。关于 EGFR 信号传导的综述请参见 Carpenter 1999, Wells 1999, Schlessinger 2002, Herbst 2004, Avraham 和 Yarden, 2011, Bartel 等人 2016, Uribe 等人 2021, Keflee 等人 2022。
英文描述
Signaling by EGFR The epidermal growth factor receptor (EGFR) is one member of the ERBB family of transmembrane glycoprotein tyrosine receptor kinases (RTK). Binding of EGFR to its ligands induces conformational change that unmasks the dimerization interface in the extracellular domain of EGFR, leading to receptor homo- or heterodimerization at the cell surface. Dimerization of the extracellular regions of EGFR triggers additional conformational change of the cytoplasmic EGFR regions, enabling the kinase domains of two EGFR molecules to achieve the catalytically active conformation. Ligand activated EGFR dimers trans-autophosphorylate on tyrosine residues in the cytoplasmic tail of the receptor. Phosphorylated tyrosines serve as binding sites for the recruitment of signal transducers and activators of intracellular substrates, which then stimulate intracellular signal transduction cascades that are involved in regulating cellular proliferation, differentiation, and survival. Recruitment of complexes containing GRB2 and SOS1 to phosphorylated EGFR dimers either directly, through phosphotyrosine residues that serve as GRB2 docking sites, or indirectly, through SHC1 recruitment, promotes GDP to GTP exchange on RAS, resulting in the activation of RAF/MAP kinase cascade. Binding of complexes of GRB2 and GAB1 to phosphorylated EGFR dimers leads to formation of the active PI3K complex, conversion of PIP2 into PIP3, and activation of AKT signaling. Phospholipase C-gamma1 (PLCG1) can also be recruited directly, through EGFR phosphotyrosine residues that serve as PLCG1 docking sites, which leads to PLCG1 phosphorylation by EGFR and activation of DAG and IP3 signaling. EGFR signaling is downregulated by the action of ubiquitin ligase CBL. CBL binds directly to the phosphorylated EGFR dimer through the phosphotyrosine Y1069 (i.e. Y1045 in the mature protein) in the C-tail of EGFR, and after CBL is phosphorylated by EGFR, it becomes active and ubiquitinates phosphorylated EGFR dimers, targeting them for degradation. Positive regulation of EGFR signaling by direct association of EGFR with accessory proteins such as AAMP and FAM83B is being investigated. For review of EGFR signaling, please refer to Carpenter 1999, Wells 1999, Schlessinger 2002, Herbst 2004, Avraham and Yarden, 2011, Bartel et al. 2016, Uribe et al. 2021, Keflee et al. 2022.
所含基因
17 个基因