The Molecular Basis of Cell Adhesion in Normal 
and Pathological Situations 
the cytoskeleton inside the cells is one of the ori- 
gins of the name "integrins." 
Using the methods of cell and molecular biol- 
ogy, we are studying the structure and function of 
fibronectins and integrins, their interactions, and 
their roles in various physiological processes, in- 
cluding development, blood clotting, inflamma- 
jjon, wound healing, and cancer. We observe reg- 
ulated expression of these molecules during 
these processes, and it is clear that these mol- 
ecules are crucial for the appropriate behavior of 
cells. For instance, altered expression of both fi- 
bronectins and integrins in tumor cells contrib- 
utes to their wayward behavior, and expression of 
these proteins is altered during wound healing. 
Using recombinant DNA methods, we can pro- 
duce specific and modified forms of fibronectins 
and integrins and thus investigate the ways in 
which they alfect the behavior of individual cell 
types. 
We have recently made progress in analyses of 
the role of the intracellular portions of various 
integrin receptors in interactions with the cyto- 
skeleton. We have also obtained detailed struc- 
tural information about the cytoskeletal protein 
talin, which is a primary candidate for interac- 
tions with integrins. We are now investigating 
possible interactions between normal and mutant 
integrins and talin. Further progress along these 
lines should help explain the effects of cell adhe- 
sion on cell structure and behavior. 
Work in the past year has uncovered evidence 
that integrins do more than provide a physical 
connection between the extracellular matrix and 
the cytoskeleton. Engagement of integrins trig- 
gers tyrosine phosphorylation inside the cells, 
strongly suggesting signaling via integrins. Inte- 
grin function can also be regulated from inside 
cells. Cells need to detach as well as attach. How 
is this regulated? We find that cell detachment 
can apparently be triggered by phosphorylation 
of the cytoplasmic domains of integrins. Thus our 
current picture of integrins is that they can medi- 
ate signaling both into and out of cells. 
To extend our understanding of the roles of 
fibronectins and integrins to intact organisms, we 
use genetic analyses in two animal systems. First, 
we are analyzing the role of integrins during the 
development of Drosophila melanogaster, a 
fruit fly that is suitable for genetic analyses. Flies 
with mutations in genes encoding integrins have 
defects in embryonic development, in muscle 
function, and in the development of wings and 
eyes. Analyses of these defects provide insights 
into the functions of these proteins. We are also 
identifying new integrin species in Drosophila. 
In the second genetic project, we have gener- 
ated strains of mice that are mutant for fibronec- 
tins. When both normal copies of the fibronectin 
gene are ablated, mouse embryos cannot proceed 
normally beyond the early developmental stage 
known as gastrulation. We have also made more- 
subtle mutations in the fibronectin gene and are 
currently analyzing their effects. These mutant 
mice, together with transgenic mice expressing 
different forms of fibronectin, should allow us to 
dissect the functions of the various forms of fibro- 
nectin in vivo. Encouraged by the progress on 
fibronectin molecular genetics in mice, we have 
also begun to generate mutations in integrin re- 
ceptor genes and in other cell adhesion mole- 
cules, particularly selectins, cell-cell adhesion 
molecules involved in the early steps of inflam- 
mation. As our analyses proceed, we will be able 
to investigate the effects of the various mutations 
on hemostasis, thrombosis, wound healing, and 
tumor development. 
These studies should provide a deeper under- 
standing of the molecular basis of cell adhesion 
and its involvement in physiological and patho- 
logical processes. This understanding, in turn, 
should provide opportunities for therapeutic 
treatments of diseases such as thrombosis and 
cancer. 
The work on cultured cells and some of the 
work on mice are supported by grants from the 
National Institutes of Health. 
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