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Feedback regulation of EGFR signalling: decision making by early and delayed loops

Key Points

  • The epidermal growth factor receptor (EGFR)/ERBB family has evolved from a primordial, simple pathway of a single ligand receptor pair to a complex signalling network. Studies in invertebrates and in mammalian systems have unveiled a web of activity-dependent regulatory loops, which fall into early and late groups.

  • In the early phase, ubiquitylation and other covalent modifications that control receptor degradation, as well as primary and secondary (backward) phosphorylation, have major roles in the immediate regulation of receptor signalling. This phase also includes very rapid turnover of a group of microRNAs (miRNAs).

  • Late regulatory mechanisms of the network comprise newly induced mRNAs, miRNAs and proteins, which account for the specificity of the response to external stimuli.

  • The dynamic behaviour of the EGFR network and similar signalling systems identifies feedback and feedforward loops as a computational core able to perform complex tasks, such as digitalization of graded signals, filtration of noise, calculation of fold induction and fixation of output. This leads to stable phenotypes.

  • Cancer and other hyperproliferation diseases harness the regulatory mechanisms of the network by weakening negative feedback and enhancing positive feedback, thereby manipulating critical time constants of the network.


Human-made information relay systems invariably incorporate central regulatory components, which are mirrored in biological systems by dense feedback and feedforward loops. This type of system control is exemplified by positive and negative feedback loops (for example, receptor endocytosis and dephosphorylation) that enable growth factors and receptor Tyr kinases of the epidermal growth factor receptor (EGFR)/ERBB family to regulate cellular function. Recent studies show that the collection of feedback regulatory loops can perform computational tasks — such as decoding ligand specificity, transforming graded input signals into a digital output and regulating response kinetics. Aberrant signal processing and feedback regulation can lead to defects associated with pathologies such as cancer.

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Figure 1: Early regulatory loops — the 'all out war'.
Figure 2: Wave-like regulation of mrNas and microrNas by egF.
Figure 3: Late regulatory loops.
Figure 4: Decision making by PC-12 cells.
Figure 5: Examples of network motifs in mammalian signalling systems.


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We thank R. Milo and members of our laboratory for comments. Our laboratory is supported by research grants from the National Cancer Institute, the Seventh Framework Program (FP7) of the European Commission, the German Research Foundation (DFG), M. Adelson and S. G. Adelson of the Medical Research Foundation, the Kekst Family Institute for Medical Genetics, the Kirk Center for Childhood Cancer and Immunological Disorders, the Women's Health Research Center funded by Bennett-Pritzker Endowment Fund, the Marvelle Koffler Program for Breast Cancer Research and the M.D. Moross Institute for Cancer Research. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair.

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S1 (box)

S2 (table)


Extracellular signal-related kinase pathway

A three-tiered kinase module in which the first kinase, RAF, phosphorylates and activates the second kinase, mitogen-activated protein kinase kinase (MEK), which phosphorylates the third kinase, extracellular signal- regulated kinase (ERK), in a two-step, non-processive reaction.


Concurrent partial loss of function of the protein product of duplicated genes, such that collaboration between respective gene products reconstitutes the full set of sub-functions attributed to the original ancestor.


Coexistence of functionally similar components offering an alternative route for signal propagation if one of the components is inactivated.

Feedback loop

A composite two-arm loop in which a protein, X, activates a downstream protein, Y, or transcriptionally induces a gene encoding Y. On activation, Y regulates X (positively or negatively).


The intake of material from the extracellular matrix or the membrane into vesicles that arise from the inward folding of the plasma membrane.

Binary switching

When a system's output can transit between two states: 'on' and 'off', with (almost) no intermediate states.

Analogue signal

A continuous signal that changes quantitatively in amplitude or concentration.

E3 ubiquitin ligase

A protein that induces the attachment of ubiquitin, a small, highly conserved regulatory protein, to a Lys on a target protein and thus targets specific protein substrates for degradation.

14-3-3 chaperone

Adaptor/scaffold proteins that form homo- and heterodimers and bind, through specialized phosphorylated peptide motifs, to various proteins that are involved in signal transduction and in cell-cycle control.

Immediate early genes

(IEGs). Genes that are induced rapidly and do not require new protein synthesis for their transcription.

RNA polymerase II

(Pol II). An enzyme that catalyses the transcription of DNA to synthesize precursors of mRNA and most known small RNAs.

Histone acetylation

Addition of an acetyl group to Lys amino acids on histone proteins, which renders DNA more accessible to transcription factors, and thus is linked to transcriptional activation.

CpG island

A genomic region that contains a relatively high content of cytosine (C) and guanine (G) dinucleotides (the 'p' refers to the phosphodiester bond linking the two bases). CpG islands are found in many mammalian promoters and unlike scattered CpGs throughout the genome, which are usually hypermethylated, promoter CpG islands are normally hypomethylated.

Epithelial–mesenchymal transition

(EMT). A phenotypic transformation of a highly polarized epithelial sheet of densely packed cells into sparse, motile cells resembling connective tissue cells. This transition involves a series of molecular switches, which are dependent on newly induced mRNAs and microRNAs.


A mode in which it is easier to maintain the system in its 'on' state than to toggle the system between 'on' and 'off'.

Network motifs

A pattern of interactions that recurs in cellular networks significantly more often than in randomized networks.


An adrenal gland tumour that originates from neural crest cells.

Feedforward loop

A regulatory pattern in which a stimulus (X) feeds into a response (Y) via more than one route: directly into Y or indirectly via Z (which interacts with Y). In a coherent feedforward loop the sign of the leg from X to Y equals the summation of the alternative leg (X-to-Z-to-Y). In any other case, the design is referred to as an incoherent feedforward loop.

Scale-free network

A non-uniform network whose connectivity (the number of edges of each of the nodes) follows a power law. Scale-free biological networks are mostly comprised of nodes with one to two edges, and several highly linked hubs with six or more edges.

Network hubs

Richly linked nodes of the network that account for most of the vulnerability of scale-free networks, as damage to one of the hubs of a network can break it up into segregated sub-graphs.

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Avraham, R., Yarden, Y. Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nat Rev Mol Cell Biol 12, 104–117 (2011).

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