表皮生长因子受体 (EGFR) 信号


 背景

表皮生长因子受体 (Epidermal growth factor receptor,EGFR) 是受体酪氨酸激酶家族 (receptor tyrosine kinase family,RTK) 中第一个被发现的原型成员。它被细胞外环境中的各种配体激活并传递细胞响应以介导各种细胞活动,包括细胞增殖、细胞存活、生长和发育。EGFR 在许多器官中有表达,异常表达与多种癌症有关。本文重点介绍了 EGFR 通路的各种信号成分及其信号转导通路。


 表皮生长因子受体 (EGFR) 和配体

ErbB 家族由四种受体组成,包括 EGFR (ErbB-1/HER1)、ErbB-2 (Neu,HER2)、ErbB-3 (HER3) 和 ErbB-4 (HER4)。该受体酪氨酸激酶家族 (RTK) 具有胞外配体结合结构域、疏水跨膜结构域和胞质酪氨酸激酶结构域。ErbB 受体被 EGF-家族的生长因子激活,其特征在于赋予结合特异性的三个二硫键。其他结构基序包括免疫球蛋白样结构域,肝素结合位点和糖基化位点1,2。EGFR 配体及其特异性受体见表 1。

表 1 EGFR 受体和配体

受体 配体
EGFR  EGF转化生长因子-α (TGF-α),双调蛋白 (AR), β 细胞素 (BTC),肝素结合表皮生长因子 (HB-EGF) 和表皮调节素 (EPR)
ErbB2
ErbB3  NRG-1 和 NRG-2
ErbB4 细胞素 (BTC) ,肝素结合 EGF 样生长因子 (HB-EGF) ,表皮调节素 (EPR) ,Tomoregulin,NRG-1,NRG2,NRG3 和 NRG4


 受体激活

受体激活是由细胞膜上的一系列事件触发的。

  • 配体结合: 每个配体与同源 ErbB 受体的胞外结构域结合
  • 受体二聚化: 配体结合诱导形成受体同源或异源二聚体3
  • 激酶结构域的激活: 羧基末端尾部关键酪氨酸残基的自磷酸化激活受体,并作为与 Src 同源 2 (SH2) 和磷酸酪氨酸结合域 (PTB) 蛋白的停靠位点,触发细胞信号传导3,4

 

图 1. EGFR 信号

图 1. EGFR 信号


 EGFR 信号

Ras/Raf 信号级联

受体: 任何两种 ErbB 受体的二聚化

关键功能:  细胞存活和细胞增殖5

受体激活后,Grb2 和 Sos 形成的复合物直接或通过衔接蛋白 Shc 结合到受体上的特定酪氨酸残基上6,7。这导致 Sos 的构象变化,从而募集和激活 Ras-GDP。Ras-GDP 激活 Raf-1,后者进一步激活通过丝裂原活化蛋白激酶 (MAPK) 介导的细胞外调节激酶 1 和 2(ERK1 和 ERK2)8,9。活化的激酶最终进入细胞核,磷酸化特定的转录因子如 Elk1 和 C-myc 以诱导细胞增殖。

磷脂酰肌醇 3-激酶/Akt 信号级联反应

受体: ErbB2 与 ErbB4 或 ErbB3 的二聚化

关键功能:  细胞生长、凋亡抵抗、细胞侵袭和迁移10

磷脂酰肌醇由 p85 和 p110 亚单位组成,这些亚单位与 ErbB 受体对接产生次级信使磷脂酰肌醇 3,4,5-三磷酸,后者进一步激活丝氨酸/苏氨酸激酶 AKT。激活后,AKT 磷酸化 mTOR 和随后介导蛋白质合成的 S6K10

信号转导和转录激活因子 (STAT) 途径

受体: ErbBc

关键功能: 肿瘤进展、肿瘤发生和血管生成11

STAT 蛋白通过 Src 同源 2 个结构域与 ErbB 受体的磷酸酪氨酸残基对接,并在二聚化上向上,转位进入细胞核,促进特定靶基因如 Myc、Nos2、p21 和细胞因子的表达 12

磷脂酶 Cγ 信号

受体:  ErbB1

关键功能: 调节离子通道、细胞迁移、钙介导的信号传导13

磷脂酶 Cγ 与 ErbB1 相互作用,水解磷脂酰肌醇 4,5-二磷酸 (PIP2) 生成肌醇 1,3,5-三磷酸 (IP3) 和 1,2 二酰甘油 (DAG)。IP3 增加细胞内钙水平,DAG 介导蛋白激酶 C (PKC) 的激活13。激活的 PKC 依次激活 MAPK 和 c-Jun NH2-末端激酶 14

Nck/PAK 信号级联

受体: ErbB1

关键功能:  细胞存活和细胞迁移15

Nck 是一种含有 SH2 结构域的衔接蛋白,与 EGF 受体结合并触发下游信号。Nck 通过 SH3 结构域激活 PAK1(p21/CDC42/Rac1 激活的激酶-1)结合。激活的 PAK1 依次激活 MEKK1(MAP/ERK 激酶激酶-1)和 MKK4/7(MAP 激酶激酶-4/7)介导的 JNKs(c-Jun 激酶)。JNK 易位至细胞核并磷酸化转录因子如 c-Fos 和 c-Jun16

Cbl 介导的内吞作用

受体: ErbB1

关键功能: 内吞作用

配体结合后,Cbl 是通过 SH2 结构域或通过 GRB2 衔接蛋白与 EGF 受体结合并触发受体溶酶体降解的底物 17

EGFR 易位至细胞核

EGF 受体具有逃避溶酶体降解并转位进入细胞核以介导生物学功能的能力。在细胞核中,这些受体促进细胞存活基因如  Cyclin D1  基因的转录,也作为 STAT 和 E2F1 转录因子的辅助因子18。EGFR 的核定位通过赋予对抗癌单克隆抗体的生长抑制作用的抗性影响疾病的严重程度19

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种类 小鼠 小鼠 小鼠 小鼠 小鼠
表达为/提取自 大肠杆菌 大肠杆菌 大肠杆菌 大肠杆菌 大肠杆菌 鼠颌下腺 大肠杆菌 鼠颌下腺 HEK 293
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 发育与疾病中的 EGFR

EGF 受体  及其配体对各器官发育有重要意义;EGFR 敲除模型显示胚胎致死性和有缺陷的组织/器官。然而,ErbB 配体的突变不显示任何致死表型,因为其他配体的互补途径补偿了突变的 ErbB 配体的废除信号。20-25  EGFR 在许多疾病中有异常激活或表达。具体而言,它们在癌症进展中的作用已得到很好的研究。表 2 总结了一些遗传改变及其表型效应。

表 2。 人类疾病中 EGFR 受体的遗传改变
 

遗传改变 意义
EGFR 突变  非小细胞肺癌 26
 结直肠癌中的西妥昔单抗耐药性 27
 非小细胞肺癌 28
 间变性和滤泡状甲状腺癌 29
 肺腺癌 30
 炎症性皮肤和肠道疾病 36
ErbB2 的过表达  胃癌和乳腺癌 31,32
ErbB2 和 ErbB3 的过表达  前列腺癌 33
EGFR 信号失调  多囊肾病,肾小球肾炎,糖尿病肾病 34
EGFR 的过表达 潜在的新一代的少突胶质细胞治疗早产儿脑白质损伤方法 35


 结论

EGFR 信号在发育中具有多效性功能,调节多种生理功能。EGF 受体的异常表达已经越来越多地涉及各种疾病。还需要更多的研究来明确揭示 EGFR 信号在脑、心脏、皮肤、肾脏、乳腺和肺等多种器官发育中的作用。寻找具有高效、持续的药物活性和较少交叉反应性以对抗抗药性癌症的新型药物仍是当前的热点研究领域。

点击 此处了解更多高质量 EGF 重组蛋白和受体的完整产品供您研究使用。

研究干细胞培养中 EGF 信号的一致性。访问我们的 干细胞学习中心 了解更多信息。

 
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