EGF receptor ligands: recent advances

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Abstract

Seven ligands bind to and activate the mammalian epidermal growth factor (EGF) receptor (EGFR/ERBB1/HER1): EGF, transforming growth factor-alpha (TGFA), heparin-binding EGF-like growth factor (HBEGF), betacellulin (BTC), amphiregulin (AREG), epiregulin (EREG), and epigen (EPGN). Of these, EGF, TGFA, HBEGF, and BTC are thought to be high-affinity ligands, whereas AREG, EREG, and EPGN constitute low-affinity ligands. This focused review is meant to highlight recent studies related to actions of the individual EGFR ligands, the interesting biology that has been uncovered, and relevant advances related to ligand interactions with the EGFR.

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Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair.

Dietmar M. W. Zaiss, William Gause, Lisa Osborne … (2015)

Type 2 inflammatory responses can be elicited by diverse stimuli, including toxins, venoms, allergens, and infectious agents, and play critical roles in resistance and tolerance associated with infection, wound healing, tissue repair, and tumor development. Emerging data suggest that in addition to characteristic type 2-associated cytokines, the epidermal growth factor (EGF)-like molecule Amphiregulin (AREG) might be a critical component of type 2-mediated resistance and tolerance. Notably, numerous studies demonstrate that in addition to the established role of epithelial- and mesenchymal-derived AREG, multiple leukocyte populations including mast cells, basophils, group 2 innate lymphoid cells (ILC2s), and a subset of tissue-resident regulatory CD4(+) T cells can express AREG. In this review, we discuss recent advances in our understanding of the AREG-EGF receptor pathway and its involvement in infection and inflammation and propose a model for the function of this pathway in the context of resistance and tissue tolerance.

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Amphiregulin exosomes increase cancer cell invasion.

James N. Higginbotham, Michelle Demory Beckler, Jonathan Gephart … (2011)

Autocrine, paracrine, and juxtacrine are recognized modes of action for mammalian EGFR ligands including EGF, TGF-α (TGFα), amphiregulin (AREG), heparin-binding EGF-like growth factor (HB-EGF), betacellulin, epiregulin, and epigen. We identify a new mode of EGFR ligand signaling via exosomes. Human breast and colorectal cancer cells release exosomes containing full-length, signaling-competent EGFR ligands. Exosomes isolated from MDCK cells expressing individual full-length EGFR ligands displayed differential activities; AREG exosomes increased invasiveness of recipient breast cancer cells 4-fold over TGFα or HB-EGF exosomes and 5-fold over equivalent amounts of recombinant AREG. Exosomal AREG displayed significantly greater membrane stability than TGFα or HB-EGF. An average of 24 AREG molecules are packaged within an individual exosome, and AREG exosomes are rapidly internalized by recipient cells. Whether the composition and behavior of exosomes differ between nontransformed and transformed cells is unknown. Exosomes from DLD-1 colon cancer cells with a mutant KRAS allele exhibited both higher AREG levels and greater invasive potential than exosomes from isogenically matched, nontransformed cells in which mutant KRAS was eliminated by homologous recombination. We speculate that EGFR ligand signaling via exosomes might contribute to diverse cancer phenomena such as field effect and priming of the metastatic niche. Copyright © 2011 Elsevier Ltd. All rights reserved.

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Amphiregulin.

Carmen Berasain, Matías Avila (2014)

Amphiregulin (AREG) is a ligand of the epidermal growth factor receptor (EGFR), a widely expressed transmembrane tyrosine kinase. AREG is synthesized as a membrane-anchored precursor protein that can engage in juxtacrine signaling on adjacent cells. Alternatively, after proteolytic processing by cell membrane proteases, mainly TACE/ADAM17, AREG is secreted and behaves as an autocrine or paracrine factor. AREG gene expression and release is induced by a plethora of stimuli including inflammatory lipids, cytokines, hormones, growth factors and xenobiotics. Through EGFR binding AREG activates major intracellular signaling cascades governing cell survival, proliferation and motility. Physiologically, AREG plays an important role in the development and maturation of mammary glands, bone tissue and oocytes. Chronic elevation of AREG expression is increasingly associated with different pathological conditions, mostly of inflammatory and/or neoplastic nature. Here we review the essential aspects of AREG structure, function and regulation, discuss the basis for its differential role within the EGFR family of ligands, and identify emerging aspects in AREG research with translational potential.

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Author and article information

Journal

Journal ID (nlm-ta): F1000Res

Journal ID (iso-abbrev): F1000Res

Journal ID (pmc): F1000Research

Title: F1000Research

Publisher: F1000Research (London, UK )

ISSN (Electronic): 2046-1402

Publication date (Electronic): 8 September 2016

Publication date Collection: 2016

Volume: 5

Electronic Location Identifier: F1000 Faculty Rev-2270

Affiliations

[1 ]Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

[2 ]Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

[3 ]Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

[4 ]Veterans Health Administration, Tennessee Valley Healthcare System, Nashville, TN, 37212, USA

Author notes

[a ] bhuminder.singh@ 123456vanderbilt.edu

[b ] robert.coffey@ 123456vanderbilt.edu

Competing interests: The authors declare that they have no competing interests.

Article

DOI: 10.12688/f1000research.9025.1

PMC ID: 5017282

PubMed ID: 27635238

SO-VID: 9a8a85ee-0789-40dd-9657-e392113defd6

License:

This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date accepted : 5 September 2016

Funding

Funded by: National Cancer Institute

Award ID: R01-CA46413

Award ID: R01-CA163563

Award ID: P50-CA95103

The work is supported by National Cancer Institute grants R01-CA46413, R01-CA163563, and P50-CA95103 to Robert J. Coffey.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

EGF receptor ligands: recent advances

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Most cited references 76

Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair.

Amphiregulin exosomes increase cancer cell invasion.

Amphiregulin.

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