Institute of Clinical Medicine, University of Oslo, Rikshospitalet, 0027 Oslo, Norway.
Carcinogenesis. 2012 May;33(5):1031-9. doi: 10.1093/carcin/bgs128. Epub 2012 Mar 20.
The oncoprotein ErbB3 is overexpressed in several human cancers, for example in pancreatic adenocarcinoma and in ovarian cancers, and ErbB3-containing heterodimers have been demonstrated to be potent signaling units in carcinogenesis. This especially applies to ErbB2-ErbB3 and epidermal growth factor receptor (EGFR)-ErbB3 heterodimers providing anti-apoptotic signaling. Relatively little is understood about the signaling of EGFR-ErbB3 heterodimers and especially about mechanisms involved in downregulation of ErbB3 from the plasma membrane. This is in contrast to EGFR homodimers, for which trafficking has been extensively characterized. In the present study, we have investigated mechanisms involved in endocytosis of ErbB3 in porcine aortic endothelial cells stably expressing either ErbB3 only or stably expressing ErbB3 and EGFR. Our data show that ErbB3 is endocytosed in the absence of added ligand, independently of its tyrosine phosphorylation state and in a clathrin-dependent manner. Functional EGFR-ErbB3 heterodimers were observed to be formed, and dimerization with ErbB3 was observed to negatively affect endocytosis of the EGFR.
癌蛋白 ErbB3 在几种人类癌症中过表达，例如在胰腺腺癌和卵巢癌中，并且已经证明 ErbB3 包含的异二聚体是致癌作用中的有效信号单元。这尤其适用于 ErbB2-ErbB3 和表皮生长因子受体 (EGFR)-ErbB3 异二聚体提供抗细胞凋亡信号。对于 EGFR-ErbB3 异二聚体的信号转导，以及特别是关于从质膜下调 ErbB3 的机制，相对了解较少。这与 EGFR 同源二聚体形成对比，EGFR 同源二聚体的运输已经得到了广泛的描述。在本研究中，我们研究了在稳定表达 ErbB3 或稳定表达 ErbB3 和 EGFR 的猪主动脉内皮细胞中，ErbB3 内吞作用涉及的机制。我们的数据表明，在没有添加配体的情况下，ErbB3 被内吞，独立于其酪氨酸磷酸化状态，并以网格蛋白依赖的方式进行。观察到功能性 EGFR-ErbB3 异二聚体的形成，并且与 ErbB3 的二聚化被观察到对 EGFR 的内吞作用产生负面影响。
