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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Collaborating with colleagues at TSRI and The Burnham Institute, TSRI Assistant Professor David Calderwood has published a paper in Science describing a vital step in inetgrin activation. Photo by Kevin Fung.