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YSCDB-1505; No. of Pages 1

Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx

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Seminars in Cell & Developmental Biology journal homepage: www.elsevier.com/locate/semcdb

Editorial

The magnificent seven: Epidermal growth factor receptor ligands

According to the pertinent literature, the special significance of the number seven can be traced back to the celestial bodies visible to the naked eye by ancient oriental astronomers and astrologists: Sun, Moon, Mercury, Venus, Mars, Jupiter, and Saturn. Be that as it may, the number seven seems to occupy a place of exceptional importance in religion, myths, legends, and folklore. Consider, for instance, the seven sacraments of the Catholic Church, the seven deadly sins put forward in early Christian teachings, the seven branches of the Jewish menorah, the seven fields in the Star of David, or the Seven Heavens, a cosmologic concept permeating many major religions. One may continue with the seven days of the week (another legacy of ancient sky-watchers), the Seven Wonders of the Ancient World, the Seven Seas, or, in our times, with countless other examples in cinema and literature. This Seminars in Cell and Developmental Biology issue deals with another example of this intriguing number: its subject are the seven ligands of the epidermal growth factor receptor (EGFR). EGFR and EGFR ligand research were born roughly 50 years ago with the purification of a “tooth-lid factor,” subsequently renamed epidermal growth factor to account for its capacity to stimulate epidermal cell proliferation [1]. Since then, research on this subject expanded at a prodigious rate, resulting in the identification of the EGFR, the related receptors ERBB2, ERBB3, and ERBB4, and of six additional EGFR ligands: transforming growth factor-␣, heparin-binding EGF-like growth factor, amphiregulin, betacellulin, epiregulin and epigen. These growth factors, initially bio-synthesized as membrane-anchored proteins, can be cleaved by specific proteases to act on neighboring cells (paracrine signaling) or on the cell of their origin (autocrine signaling). In addition, the membrane-anchored form of some family members can also directly initiate signals on adjacent cells (juxtacrine signaling), or after being packaged into extracellular vesicles called exosomes, a signaling mode named extracrine [2]. All EGFR ligands contain the so-called EGF domain, a highly conserved, ∼50 amino acids long sequence containing six cysteines that form three loops via disulfide bridges. Notably, the EGF domain of all ligands is encoded by two exons, where the first one encodes the four N-terminal cysteines, and is located adjacent to the transmembrane region of the protein. While EGF domains can be found in several other proteins, including neuregulins, the ERBB3/4 ligands, experimental evidence indicates that only the seven previously mentioned proteins can bind and activate the EGFR [3,4].

EGFR ligands have been implicated in multiple developmental, physiological, and pathological events. Not surprisingly, the breadth of biological disciplines and techniques involved is reflected in a monumental amount of scientific literature, with publications numbering in the tens of thousands. I hope that the presented approach, in which each chapter covers the most important aspects of a specific ligand, is both digestible and informative for readers. In closing, I would like to thank all authors for their contributions, which will certainly demonstrate how much progress has been made in understanding the fascinating field of EGFR ligand research and at the same time make this research area more accessible to students and scientists. I am particularly grateful to Dr. Yarden, with whom I had the pleasure of writing the chapter on epigen, for his accurate genomic searches for additional EGFR ligands, which indicated that the list of mammalian EGF-like ligands is already complete [5]. An eighth EGFR ligand would drive a coach and six horses through my introductory paragraph. References [1] Cohen S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J Biol Chem 1962;237:1555–62. [2] Singh B, Coffey RJ. Trafficking of epidermal growth factor receptor ligands in polarized epithelial cells. Annu Rev Physiol 2013;76:275–300. [3] Harris RC, Chung E, Coffey RJ. EGF receptor ligands. Exp Cell Res 2003;284:2–13. [4] Schneider MR, Wolf E. The epidermal growth factor receptor ligands at a glance. J Cell Physiol 2009;218:460–6. [5] Kochupurakkal BS, Harari D, Di Segni A, Maik-Rachline G, Lyass L, Gur G, et al. Epigen, the last ligand of ErbB receptors, reveals intricate relationships between affinity and mitogenicity. J Biol Chem 2005;280:8503–12.

Marlon R. Schneider ∗ Gene Center, LMU Munich, Munich, Germany ∗ Correspondence

to: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Feodor-Lynen-Str. 25, D-81377 Munich, Germany. Tel.: +49 89 2180 76815; fax: +49 89 2180 76849. E-mail address: [email protected] Available online xxx

http://dx.doi.org/10.1016/j.semcdb.2014.02.003 1084-9521/© 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Schneider MR. The magnificent seven: Epidermal growth factor receptor ligands. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcdb.2014.02.003

The magnificent seven: epidermal growth factor receptor ligands.

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