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EGF–ERBB signalling: towards the systems level

Key Points

  • The ERBB system consists of four receptors (ERBB1–4), two of which, ERBB2/HER2 and ERBB3 are non-autonomous. All four ERBB proteins form functional dimers after activation by epidermal growth factor (EGF)-family growth factors.

  • Recent advances in structural analysis of the receptors has revealed the mechanism of receptor dimerization, and together with the results of gene targeting in mice provide an explanation for the critical role of ERBB2/HER2 in human cancer.

  • Misregulated activation of ERBB receptors has been widely associated with human malignancies, and a number of drugs that target these receptors are in clinical use.

  • 25,000 scientific papers relate to ERBB-receptor signalling, in which hundreds of receptor interactions are described, forcing investigators to take a systems view of the network.

  • Definitions from the field of systems biology apply to the ERBB network, which is described as a robust information-processing system, with a bow-tie structure, to which we apply principles of modularity, redundancy, bistability, system controls and buffering.

  • Fragility of the system is a necessary trade-off of its robustness, a principle we exemplify when dealing with clinically approved, as well as experimental, cancer therapeutics.

  • Future analysis of the ERBB network might depend on establishing common experimental conditions, which will allow synergistic interactions between experimentalists and theoreticians in the field.

Abstract

Signalling through the ERBB/HER receptors is intricately involved in human cancer and already serves as a target for several cancer drugs. Because of its inherent complexity, it is useful to envision ERBB signalling as a bow-tie-configured, evolvable network, which shares modularity, redundancy and control circuits with robust biological and engineered systems. Because network fragility is an inevitable trade-off of robustness, systems-level understanding is expected to generate therapeutic opportunities to intercept aberrant network activation.

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Figure 1: A systems perspective of the ERBB network.
Figure 2: Structural basis for ERBB-receptor dimerization and activation.
Figure 3: Endocytosis and nuclear translocation of ERBB proteins.
Figure 4: Multiple pathways to oncogenesis.

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Acknowledgements

We thank B. Kholodenko, S. H. Wiley, M. Hatakeyama and P. De-Meyts for insightful comments. Our laboratory is supported by research grants from the National Cancer Institute, the Israel Science Foundation, the Israel Cancer Research Fund, the Prostate Cancer Foundation and the German-Israel Foundation. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair.

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Alliance for Cell Signaling (AFCS)

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Systems Biology Markup Language (SBML)

BioModels

Glossary

Receptor tyrosine kinase

Transmembrane receptor with an intrinsic ability to transfer phosphate groups to tyrosine residues contained in cellular substrates.

Heterodimeric

In contrast to a homodimer, in which two identical receptors bind to form a dimer, heterodimers are formed by two different receptors.

Mitogen activated protein kinase

(MAPK). Parallel kinase cascades lead to the activation of the four serine/threonine MAPKs (ERK, JNK, p38 and ERK5/BMK). Activation of these kinases is critical to cellular signal transduction, driving diverse cell fates.

Phosphatidylinositol 3-kinase

(PI3K). A lipid kinase, that is the initiating enzyme in a pathway that promotes cell proliferation and survival. A central downstream mediator of the pathway is the serine/threonine kinase AKT/PKB. PI3K phosphorylates the 3′ position of the inositol ring of phosphatidylinositol-4,5-bisphosphate.

Autocrine

Secretion of a ligand that stimulates the secreting cell itself.

Waved-1 and waved-2 mice

Naturally occurring mutant mice that have wavy hair. In waved-1 mice, TGFα levels are reduced, whereas waved-2 mice have a partial inactivation of the kinase domain of ERBB1, owing to a point mutation.

Endocytosis

The process of taking in materials from outside a cell in vesicles that arise by the inward folding ('invagination') of the plasma membrane.

Trabeculae

Finger-like extensions of the ventricular myocardium.

Giant strong component network (or core process)

The largest fully connected part of a network, which functions as the core of the network, and is normally the most complicated part of the network.

Evolvability

The capacity of an organism to generate heritable phenotypic variance.

Paracrine

Activation of a receptor on an adjacent cell by a secreted ligand.

Heat shock protein-90

(HSP90). A molecular chaperone that buffers the conformation and activity of a distinct subset of cellular molecules that are involved in signal transduction. HSP90 is one of the most abundant cellular proteins.

Caveolae

Cholesterol-rich membrane microdomains that are stabilized by the protein caveolin.

Clathrin-coated vesicles

Specialized vehicles of internalization from the plasma membrane, coated with a polyhedral lattice of the protein clathrin.

Emergent behaviour

Complex behaviour that cannot be predicted from the properties of system components in isolation, but only emerges when the components are put together in a functional whole.

Psoriasis

A chronic skin disorder of genetic origin that is caused by inflammation-driven hyperproliferation of epidermal cells. Appears as red, scaly elevated plaques, specifically on joints.

Atherosclerosis

A progressive disease of the arterial blood vessel. It is caused by the formation of plaques that cause narrowing and hardening of the arteries, reducing blood flow to the heart.

Bistability

Defines that the system will transit between two states, 'on' and 'off', with no, or little, intermediary states.

Network fragility

As a network evolves robustness to particular changes, this necessarily entails an increase in its vulnerability to perturbations from unexpected sources, defining its points of fragility.

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Citri, A., Yarden, Y. EGF–ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7, 505–516 (2006). https://doi.org/10.1038/nrm1962

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