Regulation of epidermal growth factor receptor signalling by inducible feedback inhibitors

Abstract

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.

Complexity of Receptor Tyrosine Kinase Signal Processing

“…RTK network topologies involve comprehensive and intricate regulatory structures of immediate and delayed feedback loops (Fig. 3) (Kiyatkin et al 2006;Amit et al 2007;Gotoh 2009;Lemmon and Schlessinger 2010;Sturm et al 2010;Avraham and Yarden 2011;Segatto et al 2011). …”

“…The transmembrane protein LRIG1 is expressed several hours after the onset of EGFR stimulation. While LRIG1 interacts with EGFR via the extracellular domain, the intracellular domain of LRIG1 recruits Cbl, thereby providing additional mechanism of Cbl-mediated EGFR degradation (Segatto et al 2011). Whereas Cbl activation depends on EGFR activity, LRIG1 reduces the number of surface EGFR molecules both in basal conditions and upon stimulation, suggesting additional mechanisms of EGFR down-regulation (Segatto et al 2011).…”

“…Mig-6/RALT is expressed within an hour after EGFR activation N. Volinsky and B.N. Kholodenko and binds the kinase domain of all ErbB receptors in a ligand-dependent manner, suppressing their catalytic activities (Gotoh 2009;Segatto et al 2011). Mig-6 targets EGFR to lysosomes and mediates EGFR degradation independently of receptor phosphorylation or ubiquitination, thus showing the second mechanism of negative regulation (Segatto et al 2011).…”

“…Kholodenko and binds the kinase domain of all ErbB receptors in a ligand-dependent manner, suppressing their catalytic activities (Gotoh 2009;Segatto et al 2011). Mig-6 targets EGFR to lysosomes and mediates EGFR degradation independently of receptor phosphorylation or ubiquitination, thus showing the second mechanism of negative regulation (Segatto et al 2011). The Mig-6 protein also contains a Cdc42/Rac interaction and binding (CRIB) domain that selectively binds an active form of the small G protein Cdc42, which is an important regulator of cell migration.…”

“…These immediate feedforward and feedback loops operate on the timescale of seconds to minutes, which are the characteristic times of the corresponding interactions or catalytic reactions. Another large group of feedback regulators, such as Sprouty, Spred, and Mitogeninducible gene-6 (Mig-6)/receptor-associated late transducer (RALT) (Gotoh 2009;Murphy et al 2010;Segatto et al 2011) requires RTKinduced gene transcription and translation. These delayed feedbacks adapt cells to a more permanent external stimulation, persisting on the timescale of tens of minutes and hours.…”