Nectins and Integrins: The Molecular Basis of 
Cell-Substratum Adhesion 
Richard O. Hynes, Ph.D. — Investigator 
Dr. Hynes is also Professor of Biology at the Massachusetts Institute of Technology. He received his under- 
graduate degree in biochemistry from the University of Cambridge and his Ph.D. degree in biology from 
the Massachusetts Institute of Technology. After several years of postdoctoral work at the Imperial Cancer 
Research Fund laboratories in london, where he initiated the early work on fibronectins, he returned to 
MIT as a faculty member. Dr. Hynes has been the recipient of a Guggenheim Fellowship and is a Fellow 
of the Royal Society of London and the American Association for the Advancement of Science. 
MOST cells in the body adhere to their neigh- 
bors and to the extracellular matrix, a com- 
plex array of proteins that comprise a fibrillar 
meshwork throughout the body. Cell adhesion 
plays important roles in the normal functions of 
cells, contributing to cellular organization, struc- 
ture, and metabolism. During embryological de- 
velopment, cell adhesion is important for the 
movements of cells that contribute to modeling 
of the embryo. In the adult, appropriate cell ad- 
hesion is necessary for numerous physiological 
processes. 
For example, in the blood, cells known as plate- 
lets adhere to the walls of blood vessels that are 
damaged and help to prevent bleeding. This 
adhesion process is essential to protect against 
hemorrhage. On the other hand, it is equally im- 
portant that platelets should not adhere at inap- 
propriate times. If they do, the result is thrombo- 
sis. Thus the control of platelet adhesion is a 
matter of life and death. Other blood cells in- 
volved in defense mechanisms during infection 
or inflammation need to adhere to the walls of 
blood vessels at the sites of infection in order to 
emigrate into the affected tissues. 
Another process involving cell adhesion and 
migration is wound healing. When skin is dam- 
aged, the skin cells migrate in over the wound to 
cover it. The processes of cell migration involved 
in wound healing have much in common with 
those occurring during development. 
A final example is that of cancer. Tumor cells 
exhibit altered adhesion, both to one another and 
to their surroundings. This altered adhesion is 
thought to be involved in the invasion and metas- 
tasis of tumor cells. 
These examples illustrate the importance of 
appropriate adhesion of cells to their surround- 
ings. Our laboratory is involved in the molecular 
analysis of these processes. We seek to under- 
stand the proteins involved in cell adhesion and 
how they control adhesion and migration of cells 
in both normal and pathological processes. 
Two main classes of proteins interest us. The 
first comprises the large proteins that make up 
the extracellular matrix. These proteins cooper- 
ate to build a fibrillar meshwork to which the 
cells attach and on and through which they mi- 
grate. We have investigated several of these pro- 
teins, which we refer to as "nectins" to denote 
their role in binding to cells. Fibronectins, a 
closely related group of proteins all encoded by a 
single gene, are the best understood of these nec- 
tins. We and others have analyzed the functions 
and the structure of these proteins. This work is 
leading to a deeper understanding of their roles 
in cell behavior. For example, it is now known 
that fibronectins have several sites in each mole- 
cule that bind cells. The detailed structure of 
these binding sites is being elucidated. One in- 
triguing observation is that fibronectins share 
with many other nectins a common recognition 
site made up of only three amino acids. This site 
(designated RGD in the single-letter amino acid 
code) is recognized by receptor molecules on 
cell surfaces. This interaction can be blocked by 
antibodies to the nectins or to the receptors, 
which are known as integrins, or by competitor 
peptides containing the RGD sequence. Such 
blockades interfere with the cell-adhesive inter- 
actions involved in the physiological processes 
discussed above. Recent work has identified 
other cell-binding sites within fibronectins, 
which are recognized by different receptors. The 
interaction of these cells with these molecules is 
complex, which is as expected, given the partici- 
pation of cell adhesion in many diverse cellular 
functions. 
Our second major focus of interest is the family 
of integrin receptors. These comprise a family of 
related cell surface receptors, each composed of 
two subunits. Each integrin receptor has a partic- 
ular specificity for certain nectins and mediates 
the interactions of cells with the extracellular 
matrix. In addition, the integrins connect to the 
inside of the cell, where they mediate interac- 
tions with the internal structures, or cytoskele- 
ton, of the cell that are involved in the shape, 
organization, and migration of cells. This integra- 
tion of the organization of the extracellular ma- 
trix with the cytoskeleton is one of the origins of 
the name "integrins." 
We have recently made progress in analyses of 
the role of the intracellular portions of integrin 
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