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Untangling the ErbB signalling network

Key Points

  • The four ErbB receptors and their many neuregulins and EGF-like ligands form a layered signalling network. The network structure allows the diversification, tuning and robustness of cell-to-cell signalling.

  • The network evolved from a simple signalling module that controls inductive morphogenesis in invertebrates. In mammals, specific ligands and their respective homo- or heterodimeric ErbB complexes specify different cell lineages.

  • Oncogenic animal viruses harness the network through diverse molecular processes that promote ErbB signalling or prevent it from being switched off.

  • Autocrine loops, mutant ErbB1 molecules and enhanced expression of ErbB receptors are frequently observed in human cancers of epithelial and neuronal origins. Most frequent is overexpression of ErbB2, a ligandless co-receptor that amplifies ErbB signalling.

  • Current attempts to block the network in human disease include small-molecule inhibitors of tyrosine kinases and chaperones, and various gene-therapy strategies. But immunotherapy directed at ErbB2 is already widely used, in combination with chemotherapy, to inhibit metastasizing breast cancers.

  • Future pharmacological advances and deeper understanding of the network will allow selective inhibition or activation of its many routes, with the aim of curing neuronal and skin disorders, as well as cancer.

Abstract

When epidermal growth factor and its relatives bind the ErbB family of receptors, they trigger a rich network of signalling pathways, culminating in responses ranging from cell division to death, motility to adhesion. The network is often dysregulated in cancer and lends credence to the mantra that molecular understanding yields clinical benefit: over 25,000 women with breast cancer have now been treated with trastuzumab (Herceptin®), a recombinant antibody designed to block the receptor ErbB2. Likewise, small-molecule enzyme inhibitors and monoclonal antibodies to ErbB1 are in advanced phases of clinical testing. What can this pathway teach us about translating basic science into clinical use?

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Figure 1: The ErbB signalling network.
Figure 2: Crosstalk between the ErbB network and other signalling pathways.
Figure 3: Signalling by ErbB homodimers in comparison with ErbB2-containing heterodimers.
Figure 4: Therapeutic strategies for blocking the ErbB signalling network.
Figure 5: Molecular diagnosis of breast cancer.

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Acknowledgements

Y.Y. acknowledges support by the Israel Science Fund, the US Army Medical Research and Material Command and the M.D. Institute for Cancer Research.

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DATABASE LINKS

ErbB1

NRGs

ErbB3

ErbB4

ErbB2

EGF

epiregulin

NRG1β

betacellulin

PI(3)K

Shc

p70S6K

PKC

Akt

Grb7

fos

jun

myc

zinc finger

Sp1

Egr1

GABP

Grb2

phospholipase Cγ

Src

Pyk2

arrestin

Jak2

interleukin-6

TGF-α

Drosophila EGF receptor

NRG1

Herceptin

p27Kip1

Rb

p130

C225

Hsp90

amphiregulin

Vein

Gurken

Spitz

Argos

FURTHER INFORMATION

The tumour gene database

ENCYCLOPEDIA OF LIFE SCIENCES

Drosophila embryo: dorsal–ventral specification

Glossary

MESENCHYME

Immature connective tissue that consists of cells embedded in extracellular matrix.

NEUREGULINS

EGF-like ligands whose primary receptor is ErbB3 and/or ErbB4. Four types of neuregulin are known.

STROMA

Supporting connective tissue in which a glandular or other epithelium is embedded.

HUMANIZED MONOCLONAL ANTIBODY

An antibody, usually from a rodent, engineered to contain mainly human sequences. This process reduces the immune response to the antibody in humans.

ADAPTOR PROTEINS

Proteins that augment cellular responses by recruiting other proteins to a complex. They usually contain several protein–protein interaction domains.

EGF-LIKE DOMAIN

A motif with 50 amino acids, including six cysteine residues and a mainly β-sheet structure, found in all ErbB-binding growth factors and in extracellular matrix proteins.

IMMUNOGLOBULIN-LIKE DOMAIN

A protein domain composed of two β-pleated sheets held together by a disulphide bond.

METALLOPROTEINASES

Proteinases that have a metal ion at their active sites.

MESODERM

The middle germ layer of the developing embryo. It gives rise to the musculoskeletal, vascular and urinogenital systems, and to connective tissue (including that of the dermis).

ECTODERM

The outermost germ layer of the developing embryo. It gives rise to the epidermis and the nerves.

AKT PATHWAY

Akt (or protein kinase B) is a serine/threonine protein kinase activated by the phosphatidylinositol-3-OH kinase pathway that activates survival responses.

STRESS-ACTIVATED PROTEIN KINASES

Members of the mitogen-activated protein kinase (MAPK) family that respond to stress. They include the Jun amino-terminal kinases (JNKs) and the p38 MAPKs.

UBIQUITIN LIGASES

Enzymes that catalyse the last stage of ubiquitylation, in which the small protein ubiquitin is transferred from a ubiquitin-conjugating enzyme (UBC or E2) to its target protein. They are also known as E3 enzymes.

GAPS

Proteins that inactivate small GTP-binding proteins, such as Ras family members, by increasing their rate of GTP hydrolysis.

GLIA

Supporting cells of the nervous system, including oligodendrocytes and astrocytes in the central nervous system, and Schwann cells in the peripheral nervous system. Glia surround neurons, providing mechanical and physical support, and electrical insulation between neurons.

SCHWANN CELLS

Cells that produce myelin and ensheath axons in the peripheral nervous system.

TRABECULAE

Finger-like projections of cardiac muscle cells that form ridges in the ventricular wall.

SYMPATHETIC GANGLIA

Clusters of sympathetic neurons in which a glandular or other epithelium is embedded.

NEURAL CREST

A group of embryonic cells that separate from the embryonic neural plate and migrate, giving rise to the spinal and autonomic ganglia, peripheral glia, chromaffin cells, melanocytes and some haematopoietic cells.

CLONAL EXPANSION

Growth of a population of cells from a single precursor cell.

CARCINOMA

A malignant tumour of epithelial origin.

PROGNOSIS

The likely outcome or course of a disease.

ANDROGEN-DEPENDENT PROSTATE CANCER

An early form of prostate cancer that is responsive to androgens and anti-androgen therapy.

AUTOCRINE

Activation of cellular receptors by ligands produced by the same cell.

GENE AMPLIFICATION

A differential increase in a specific portion of the genome. Amplification is associated with neoplastic transformation and acquisition of drug resistance.

DUCTAL BREAST CANCER

Cancer arising from the lining of the milk ducts, as opposed to the lobules of the breast (lobular breast cancer).

ANEUPLOIDY

An abnormal number of chromosomes caused by their inaccurate segregation during cell division.

FLUORESCENCE IN SITU HYBRIDIZATION

Visualizing a genetic marker on a chromosome by using a fluorescently labelled polynucleotide probe that hybridizes to a gene on a chromosome during metaphase.

FARNESYLTRANSFERASE INHIBITORS

Inhibitors that block the activity of Ras by preventing the addition of a farnesyl group that targets it to the plasma membrane.

TYRPHOSTINS

A type of tyrosine kinase inhibitor.

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Yarden, Y., Sliwkowski, M. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2, 127–137 (2001). https://doi.org/10.1038/35052073

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