The Molecular Basis of Cell Adhesion in Normal 
and Pathological Situations 
Richard O. Hynes, Ph.D. — Investigator 
Dr. Hynes is also Professor of Biology and Director of the Center for Cancer Research at the Massachusetts 
Institute of Technology. He received his undergraduate 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 his 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 and 
structure, proliferation, and metabolism. During 
embryological development, cell adhesion is im- 
portant for the movements of cells that contrib- 
ute to modeling of the embryo. In the adult, ap- 
propriate cell adhesion 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 ad- 
hesion process is essential to protect against hem- 
orrhage. On the other hand, it is equally impor- 
tant that platelets should not adhere at 
inappropriate times. If they do, the result is 
thrombosis. Thus the control of platelet adhesion 
is a matter of life and death. Other blood cells 
involved in defense mechanisms during infection 
or inflammation need to adhere to the walls of 
blood vessels at the sites of infection 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 molecular anal- 
yses of these processes. We seek to understand 
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. The different forms of fibronectin are gener- 
ated by alternative RNA splicing. We and others 
have analyzed in detail 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 fibro- 
nectins have several sites in each molecule that 
bind cells. The detailed structure of these bind- 
ing sites is being elucidated. One intriguing ob- 
servation 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 rec- 
ognized 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 contain- 
ing the RGD sequence. Such blockades interfere 
with the cell-adhesive interactions involved in 
the physiological processes discussed above. Re- 
cent work has identified other cell-binding sites 
within fibronectins, which are recognized by dif- 
ferent receptors. Cells interact with these mole- 
cules in a complex fashion, which is as expected, 
given the participation 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 cytoskeleton 
of the cell that are involved in the shape, organiza- 
tion, and migration of cells. This integration of 
the organization of the extracellular matrix with 
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