Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA.
Biochem J. 2012 Nov 1;447(3):417-25. doi: 10.1042/BJ20120724.
HER2 (human epidermal growth factor receptor-2)-amplified tumours are characterized by constitutive signalling via the HER2-HER3 co-receptor complex. Although phosphorylation activity is driven entirely by the HER2 kinase, signal volume generated by the complex is under the control of HER3, and a large capacity to increase its signalling output accounts for the resiliency of the HER2-HER3 tumour driver and accounts for the limited efficacies of anti-cancer drugs designed to target it. In the present paper we describe deeper insights into the dynamic nature of HER3 signalling. Signalling output by HER3 is under several modes of regulation, including transcriptional, post-transcriptional, translational, post-translational and localizational control. These redundant mechanisms can each increase HER3 signalling output and are engaged in various degrees depending on how the HER3/PI3K (phosphoinositide 3-kinase)/Akt/mTOR (mammalian target of rapamycin) signalling network is disturbed. The highly dynamic nature of HER3 expression and signalling, and the plurality of downstream elements and redundant mechanisms that function to ensure HER3 signalling throughput identify HER3 as a major signalling hub in HER2-amplified cancers and a highly resourceful guardian of tumorigenic signalling in these tumours.
HER2（人表皮生长因子受体-2）扩增的肿瘤的特征是通过 HER2-HER3 共受体复合物的组成型信号传导。虽然磷酸化活性完全由 HER2 激酶驱动，但该复合物产生的信号量受 HER3 控制，并且其信号输出的大容量增加解释了 HER2-HER3 肿瘤驱动因素的弹性，并解释了旨在靶向它的抗癌药物的有限疗效。在本文中，我们描述了对 HER3 信号转导动态性质的更深入了解。HER3 信号转导的输出受几种调节模式的控制，包括转录、转录后、翻译、翻译后和定位控制。这些冗余机制都可以增加 HER3 信号转导的输出，并根据 HER3/PI3K（磷酸肌醇 3-激酶）/Akt/mTOR（雷帕霉素的哺乳动物靶标）信号网络的干扰程度在不同程度上参与。HER3 表达和信号转导的高度动态性质，以及确保 HER3 信号转导通量的下游多个元素和冗余机制，将 HER3 鉴定为 HER2 扩增癌症中的主要信号枢纽，并且是这些肿瘤中致癌信号的高度足智多谋的守护者。
