The Oncologist, Vol. 8, No. 5, 496–497,
October 2003
© 2003 AlphaMed Press
The Molecular Perspective: Epidermal Growth Factor
David S. Goodsell
Correspondence:
David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu Website: http://www.scripps.edu/pub/goodsell
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LEARNING OBJECTIVES
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After completing this course, the reader will be able to:
Describe the structure and function of epidermal growth factor and its role in cancer development and treatment.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
In the human body, cells must ask for permission to multiply. This is essential during the perfectly orchestrated growth that shapes an embryo, and is also essential in later life to restrict growth to the few places where it is needed, such as wounds that need to be healed. Normally, tissues communicate through a flurry of growth factors, passed from cell to cell to control growth levels and ensure that cells stay within the normal limits. Cancer cells, however, often acquire the ability to give themselves this permission, so they can grow without worrying about the consequences to their neighbors. Epidermal growth factor (EGF) and its receptor are one place where cancer cells short-circuit the normal controls.
EGF is part of a complex network of growth factors and receptors that together help to modulate the growth of cells. EGF is released by cells, and then is picked up either by the cell itself, stimulating its own growth, or by neighboring cells, stimulating their ability to divide. Receptors on the surface of the cell bind to EGF and relay the signal inside. When the receptor binds to EGF, it is activated by forming a dimer with other receptors. Four similar receptors have been discovered: the EGF receptor and three variants. These may dimerize with themselves, or mix-and-match to form heterodimers with the other types. The set of growth factors that interacts with these receptors is even more varied, with a dozen or so known examples, including EGF, transforming growth factor-
, and a number of neuregulins. As you can imagine, this allows much subtlety in the messages sent and delivered by this growth-regulatory signaling network.
The receptor is composed of a single chain with many functional parts, as shown in Figure 1
. It is found in the cell membrane, with one portion facing out to receive the message and one portion facing inward to relay the message to the cell machinery. The outer portion forms an EGF-binding domain. It is composed of four articulated parts: two globular parts that grip EGF and two rod-shaped linkers that are rigidified by dozens of cysteine amino acids. When this multi-part domain binds to EGF, it changes shape, releasing one of the long, cysteine-rich sections. This allows the receptor to dimerize with other receptors. As shown in Figure 2, this mode of dimerization came as something of a surprise.
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Figure 1. When epidermal growth factor is not bound, the EGF receptor folds into an inactive form that cannot dimerize. In the EGF-binding domain, the many cysteine amino acids are colored yellow. EGF binds in the big groove at the top. The active site of the tyrosine kinase domain has a drug bound, shown in purple. The drug binds in the site normally occupied by ATP, which provides phosphate groups for the kinase reaction. Atomic coordinates for this and Figure 2 were taken from entries 1jl9, 1nql, 1m17, and 1ivo at the Protein Data Bank (www.pdb.org). Atomic structures are not available for the portion that crosses the membrane or the small portion at the end of the chain, so they are shown schematically.
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Figure 2. When EGF (in red) binds to its receptor, the external domain changes shape, allowing dimerization. This brings the two kinase domains close to one another, allowing them to add phosphates to each other and activating the signaling process. Many hormone receptors act by binding to either side of a hormone, with the hormone in the center. The EGF receptor, surprisingly, forms dimers with the growth factors on opposite sides of the dimer, far from the point of contact between the two receptors.
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The part of the receptor on the inside of the cell is a tyrosine kinase enzyme. When the receptor dimerizes, these kinases add phosphate groups to tyrosine residues on the neighboring chain. Signaling proteins inside the cell then bind to these new phosphorylated tyrosines, initiating the signaling cascade that ultimately initiates DNA synthesis and cellular growth.
Many aggressive types of cancer have overactive signaling through the epidermal growth factor system. They either create excess amounts of the growth factor or develop mutant forms of the receptor that are unnaturally active. Researchers are attacking this problem by blocking the action of the receptor, attacking it at both ends. On the outside, we can treat the cancer cells with antibodies that block the binding of the growth factor. On the inside, we can use drugs that block the active site of the kinase, stopping it from transmitting the message when EGF binds. The growing body of structural and genomic data on these receptors has streamlined the discovery of these drugs, which are among the first of anticancer drugs to be developed by rational drug design methods.
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ADDITIONAL READING
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Yarden Y. The EGFR family and its ligands in human cancer: signaling mechanisms and therapeutic opportunities. Eur J Cancer 2001;37(suppl 4):S3–S8.
Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000;103:211–225.[CrossRef][Medline]
Shawver LK, Slamon D, Ullrich A. Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell 2002;1:117–123.[CrossRef][Medline]
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