The Oncologist, Vol. 7, No. 5, 467–468,
October 2002
© 2002 AlphaMed Press
FUNDAMENTALS OF CANCER MEDICINE |
The Molecular Perspective: Cadherin
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: - Gain a basic understanding of the structure and function of cadherins and their role in cancer metastasis.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
Cadherins begin their work in our first few hours of our life. Cadherins are adhesive molecules that glue our cells together. Early in the development of an embryo, they link the dividing cells together in their proper orientation, guiding the shape and form of the growing individual. In our adult body, cadherins connect cells throughout the body providing the glue that gives form to our different tissues. When cadherins fail in their function, cells lose their ability to hold onto one another. In the case of cancer, this allows individual cells to separate from a solid tumor. They are then free to wander through the body and form metastases.
Cadherins are long proteins composed of several modules linked together like beads on a string, as shown in Figure 1
. They extend from the surface of a cell and, with the help of calcium ions, adhere to cadherins on neighboring cells. This interaction is specific, allowing nerve cells to connect to other nerve cells and stomach cells to connect with other stomach cells. Many different types of cadherins are made by our cells, each with a different adhesive function used in different parts of the body.
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Figure 1. Cadherin is composed of a single protein chain that folds into a series of domains. On the outside of the cell, there are five compact domains. Calcium ions, shown here as blue spheres, bind at the junction between the domains. They provide stability and are essential for proper adhesive function. The adhesive site is in the uppermost domain and relies on a key tryptophan amino acid, shown here in red. Inside the cell, there is a small domain that interacts with catenins and other proteins that bind to the cytoskeleton. This region is shown as a schematic here, with the cell membrane in green. Coordinates for the extracellular region were taken from entry 1l3w at the Protein Data Bank (www.pdb.org).
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Cadherins extend through the cell membrane and inside the cell, they link tightly to the cytoskeleton forming a sturdy brace. In some cases, a circular patch of cadherin is linked to intermediate filaments inside the cell, forming a spot desmosome. These are small spot-welds that glue cells together. In other cases, an extended belt of cadherin is linked to actin filaments inside the cell, forming adherens junctions (or belt desmosomes), as shown in Figure 2. In these junctions, catenin proteins form the link between the short tail of cadherin and the long actin filaments.
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Figure 2. Cadherins extend from the surface of the cell and attach to cadherins on a neighboring cell. Here, a portion of an adherens junction is shown, with cadherin molecules in red. The two cell membranes are shown in light green, and the cadherin molecules are linked in the space between the two cells. Just inside each cell, catenin molecules (in green) link the cadherins to actin filaments (in blue).
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The failure of cadherin is one of the key steps in the creation of metastases. In order to metastasize, tumor cells must gain the ability to separate from their neighbors and travel through the blood to distant sites. Cadherin function is lost in different ways in different cancers. Some have mutations that reduce the production of cadherin, stopping its function at the source. Other tumors have a mutation in the protein itself, destroying its adhesive function. Others create a protein-cutting enzyme that attacks cadherin. Whatever the mechanism, the integrity of the tissue is destroyed and free cancer cells are released, ready to invade healthy tissues.
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ADDITIONAL READING
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Bracke ME, Van Roy FM, Mareel MM. The E-catherin/catenin complex in invasion and metastasis. Curr Topics Microbio Immunol 1996;213:123–161.
Nollet F, Kools P, Van Roy F. Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members. J Mol Biol 2000;299:551–572.[CrossRef][Medline]
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