Department of Experimental Oncology, Regina Elena Cancer Institute, 00158 Rome, Italy.
J Cell Sci. 2011 Jun 1;124(Pt 11):1785-93. doi: 10.1242/jcs.083303.
Signalling by the epidermal growth factor receptor (EGFR) controls morphogenesis and/or homeostasis of several tissues from worms to mammals. The correct execution of these programmes requires the generation of EGFR signals of appropriate strength and duration. This is obtained through a complex circuitry of positive and negative feedback regulation. Feedback inhibitory mechanisms restrain EGFR activity in time and space, which is key to ensuring that receptor outputs are commensurate to the cell and tissue needs. Here, we focus on the emerging field of inducible negative feedback regulation of the EGFR in mammals. In mammalian cells, four EGFR inducible feedback inhibitors (IFIs), namely LRIG1, RALT (also known as MIG6 and ERRFI1), SOCS4 and SOCS5, have been discovered recently. EGFR IFIs are expressed de novo in the context of early or delayed transcriptional responses triggered by EGFR activation. They all bind to the EGFR and suppress receptor signalling through several mechanisms, including catalytic inhibition and receptor downregulation. Here, we review the mechanistic basis of IFI signalling and rationalise the function of IFIs in light of gene-knockout studies that assign LRIG1 and RALT an essential role in restricting cell proliferation. Finally, we discuss how IFIs might participate in system control of EGFR signalling and highlight the emerging roles for IFIs in the suppression of EGFR-driven tumorigenesis.
表皮生长因子受体（EGFR）的信号转导控制着从蠕虫到哺乳动物的几种组织的形态发生和/或动态平衡。这些程序的正确执行需要产生适当强度和持续时间的 EGFR 信号。这是通过正反馈和负反馈调节的复杂电路来实现的。反馈抑制机制及时和空间上限制 EGFR 活性，这是确保受体输出与细胞和组织需求相称的关键。在这里，我们专注于哺乳动物中 EGFR 诱导性负反馈调节的新兴领域。在哺乳动物细胞中，最近发现了四个 EGFR 诱导性负反馈抑制剂（IFIs），即 LRIG1、RALT（也称为 MIG6 和 ERRFI1）、SOCS4 和 SOCS5。EGFR IFIs 是在 EGFR 激活触发的早期或延迟转录反应的背景下从头表达的。它们都通过几种机制结合到 EGFR 上并抑制受体信号，包括催化抑制和受体下调。在这里，我们回顾了 IFI 信号的机制基础，并根据基因敲除研究合理化了 IFI 的功能，这些研究赋予了 LRIG1 和 RALT 在限制细胞增殖方面的重要作用。最后，我们讨论了 IFIs 如何参与 EGFR 信号的系统控制，并强调了 IFIs 在抑制 EGFR 驱动的肿瘤发生中的新兴作用。
