The Tail End of Integrin Activation
By Jason Socrates Bardi
There is no shortage of information on the Internet about
integrins.
A recent Google search for the word "integrin," in fact,
turned up 263,000 web pages devoted to the structure, chemistry,
and biology of this important family of cell-surface proteins,
which are involved in everything from early embryonic development
to the development of heart diseases and cancer later in life.
There was even one site that boasted an integrin chat room.
Such an ocean of preexisting information begs the question,
is there anything more to say?
In this case, the answer is an emphatic yes.
Written by a team of scientists from The Scripps Research
Institute (TSRI) and its neighboring La Jolla institution,
The Burnham Institute, a paper appearing in this week's issue
of the journal Science describes a crucial final step
in the process of integrin activation—the binding of
a protein called talin.
"Talin is required for the activation process," says TSRI
Assistant Professor David Calderwood, who led the study. "This
interaction is the last step."
The study is interesting because understanding the way in
which integrins are activated is crucial to understanding
their function in all the physiological processes in which
integrins are involved.
Integrins and Platelets
Integrins are large binary protein complexes made up of
two different types of polypeptide chains (called the alpha
and beta subunits) that come together to form a "heterodimer"
that is expressed on the surface of a cell.
They are somewhat top-heavy. A huge portion of the protein
is extracellular and sticks out on the outside of the cell,
and just a tiny tail of a few dozen amino acids protrudes
through the membrane on the inside of the cell.
The large extracellular portions are the domains that bind
to molecules on the outside of the cells and mediate the interactions
of the cell with other cells.
If tissues were trains and cells were the boxcars, then
integrins would be the hooks that hold the boxcars together.
They hold cells together and keep them bound to one another
and to the extracellular matrix maintaining the integrity
of tissues in mammals and other multicellular organisms. They
are also important in early development for the formation
of distinct tissues.
But integrins do more than just hold cells together. They
are also crucial mediators of a host of other normal and abnormal
biological processes. They are important for inflammation;
they are essential for platelet aggregation after vascular
injury; and they are involved in cell motility. As such, they
are involved in diseases where the normal mechanisms of platelet
aggregation go awry—as in heart attacks and strokes—and
are implicated in cancer metastasis.
Not surprisingly, scientists have for years been interested
in what integrins do, how they are involved in conditions
like cancer, heart attacks, and stroke, and whether the mechanisms
of integrin activation could be modulated to improve the prognosis
of patients.
For instance, one of the molecules to which integrins bind
is fibrinogen, a circulating dimeric protein that is present
in large amounts in the blood and can bind integrins at both
ends. This interaction is essential for mediating the aggregation
of platelets—those flat, molecule-filled cytoplasmic
disks in the blood.
Platelets are covered with integrins (typically 80,000 are
on the surface of any given platelet). But the integrins need
to be activated to bind fibrinogen. When they are not active,
the platelets flow in the blood without sticking to each other
or to blood vessel walls.
An injury will cause the integrins on the surface of platelets
to become activated. The activated integrins then bind to
fibrinogen, which then bind to other activated integrins on
other platelets, cross-linking many platelets into a massive
thrombus.
The body tightly controls this cascading reaction. Not enough
thrombus formation could lead to massive blood loss, and too
much could lead to a lethal, occlusive thrombus, causing a
heart attack or stroke.
Understanding how integrins are activated, then, is a crucial
question for scientists. Calderwood and his Department of
Cell Biology colleagues, TSRI Professors Mark Ginsberg and
Sanford Shattil investigated this topic thanks to support
from the Program in Hemostasis and Thrombosis at the National
Heart, Lung, and Blood Institute, one of the National Institutes
of Health, and from the American Heart Association.
The Vital Step in Integrin Activation
How exactly the activation of integrins is controlled by
the body has been an open question for several years, but
in the last decade more and more evidence has pointed to the
importance of the tiny tails of the integrins inside the cells.
How these small cytoplasmic domains activate integrins has
been studied for some time. In fact, says Ginsberg, many—perhaps
thousands—of scientific papers published on various steps
in the pathway of integrin activation and molecules that perturb
these steps.
What has not been known, until now, is the final step in
this activation process.
The talin protein turns out to be key. Though the mechanism
is not completely clear, Calderwood, Ginsberg, and their colleagues
have evidence that shows when talin binds to the beta subunit
of integrin, it causes a conformational change in the integrin,
which is propagated across the membrane, changing the structures
of the integrin domains on the outside.
"This is the vital step," says Calderwood. "Talin binds
to the cytoplasmic tail, and that passes a signal that changes
the large extracellular domain."
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