Earp H S, Dawson T L, Li X, Yu H
Department of Medicine, University of North Carolina, Chapel Hill 27599, USA.
Breast Cancer Res Treat. 1995 Jul;35(1):115-32. doi: 10.1007/BF00694752.
The EGF receptor (EGFR) and HER2 are members of a growth factor receptor family. Overexpression of either protein in advanced breast cancer correlates with poor prognosis. EGF stimulates growth by binding to EGFR, activating the receptor's intracellular tyrosine kinase. The initial consequence is phosphorylation of specific tyrosine-containing sequences in the receptor's carboxyl terminus. These phosphotyrosines serves as high affinity recognition sites for proteins that, in turn, transmit the growth signal inside the cell. Mechanistic studies suggest that EGF binds to a single EGFR, triggering dimerization with another like receptor molecule. This dimerization is thought to initiate the tyrosine kinase activation. The EGF receptor family was recently expanded with the sequencing of HER3 and HER4. Each of the four family members was postulated to regulate a unique growth or differentiation signaling repertoire when activated by a receptor-specific ligand. However, new data from numerous laboratories suggest that EGFR family members may play a complex and ultimately more flexible role in signaling by forming heterodimers between family members, e.g. EGFR:HER2 or HER4:HER2. These heterodimers may form even when only one member of the pair binds its ligand. This review summarizes current work on heterodimerization and attempts to predict the consequences for downstream signaling. In brief, when compared to ligand-dependent receptor homodimers comprised of two proteins with the same internalization sequence and phosphorylated tyrosine residues, heterodimers are likely to: i) expand substrate selection and downstream signaling pathway activation; ii) promote interaction between sets of substrates in the mixed receptor complexes that would not ordinarily be physically juxtaposed; iii) alter the duration of receptor signaling by changing rates of receptor internalization, ligand loss, kinase inactivation, recycling, etc.; and iv) alter rates of receptor and substrate dephosphorylation. In addition to understanding interactions of heterodimers with the internalization machinery, identification of receptor-specific substrates and binding proteins for each EGFR family member will be necessary to explicate the role of heterodimers in growth and differentiation.
表皮生长因子受体（EGFR）和人表皮生长因子受体2（HER2）是生长因子受体家族的成员。在晚期乳腺癌中，这两种蛋白中任何一种的过表达都与预后不良相关。表皮生长因子（EGF）通过与EGFR结合来刺激生长，激活受体的细胞内酪氨酸激酶。最初的结果是受体羧基末端特定含酪氨酸序列的磷酸化。这些磷酸化酪氨酸作为蛋白质的高亲和力识别位点，进而在细胞内传递生长信号。机制研究表明，EGF与单个EGFR结合，引发与另一个同类受体分子的二聚化。这种二聚化被认为会启动酪氨酸激酶的激活。随着HER3和HER4的测序，表皮生长因子受体家族最近得到了扩展。这四个家族成员中的每一个在被受体特异性配体激活时，都被假定为调节一套独特的生长或分化信号通路。然而，众多实验室的新数据表明，表皮生长因子受体家族成员可能通过在家族成员之间形成异源二聚体，如EGFR:HER2或HER4:HER2，在信号传导中发挥复杂且最终更灵活的作用。即使二聚体中的只有一个成员结合其配体，这些异源二聚体也可能形成。这篇综述总结了目前关于异源二聚化的研究工作，并试图预测其对下游信号传导的影响。简而言之，与由具有相同内化序列和磷酸化酪氨酸残基的两种蛋白质组成的配体依赖性受体同源二聚体相比，异源二聚体可能会：i）扩大底物选择范围并激活下游信号通路；ii）促进混合受体复合物中通常不会物理并列的底物组之间的相互作用；iii）通过改变受体内化、配体丢失、激酶失活、再循环等速率来改变受体信号传导的持续时间；iv）改变受体和底物的去磷酸化速率。除了了解异源二聚体与内化机制的相互作用外，确定每个表皮生长因子受体家族成员的受体特异性底物和结合蛋白对于阐明异源二聚体在生长和分化中的作用也将是必要的。
