Integrin's Regulation of Rac—Potentially Profound Consequences for Cancer and Cardiovascular Diseases

By Jason Socrates Bardi

Cell biology was born in the mid-1600s, when Robert Hooke first described the tiny box-like structures he saw when observing thin slices of cork through a primitive microscope of his own design. (The cork "cells" reminded him of the cells of a monastery).

Three hundred and fifty years later, we know how dynamic and active cells really are, with thousands of different types of proteins, lipids, nucleic acid strands, salts, buffers, and other compounds working in concert to accomplish the basic processes of life. But there is still much that we don't know. Miguel del Pozo, Assistant Professor of the Departments of Immunology and Cell Biology at The Scripps Research Institute is filling in these gaps by studying one of the most fundamental aspects of cellular biology—the control of many of the cell's basic functions through signaling molecules.

In this week's issue of the journal Science, del Pozo and his colleagues describe the regulation of a signaling molecule called Rac by another class of cellular proteins known as integrins. This regulation may have profound consequences for health problems such as cancer and cardiovascular disease.

Integrins, Microdomains, and the Regulation of Rac

Cells in the body are exposed to many external signals—information that receptors on the surface of cells transduce into signals on the inside of the cell. Once there, the information is integrated with other signals to determine the cell's fate—whether it migrates, mitoses, or commits suicide.

Some of the most interesting players in this regard are integrins, large protein complexes that stick out on the surface of a cell, binding to other molecules, mediating cell-cell interactions, and maintaining the integrity of tissues in mammals and other multicellular organisms. Integrins are also important in early development for the formation of distinct tissues and are crucial mediators of a host of other normal and abnormal biological processes: inflammation, blood clotting, and cell motility to name a few.

Accordingly, integrins are implicated in diseases—such as heart attacks, strokes, and metastatic cancer—where these normal biological functions go awry. Not surprisingly, scientists have for years been interested in whether the mechanisms of integrin activation can be understood and modulated to improve the prognosis of patients.

One of the many signaling pathways that integrins regulate is the Rac pathway. Rac is a small GTP binding protein found in the ruffles and edges of cells that is important for polarizing, for cell migration, for expressing genes within a cell, and for cell cycle progression.

According to the research by del Pozo and his colleagues, integrins regulate Rac by regulating membrane compartments known as microdomains. Microdomains are parts of the plasma membrane that are high in cholesterol, certain other types of lipids, and proteins. This composition changes the local chemistry within the microdomain and forms a platform membrane that is more ordered and more stable than the surrounding membrane.

Scientists had previously speculated that these microdomains were involved in signaling, but this was hard to verify because they are difficult to see under the microscope. But del Pozo and his colleagues were able to determine that these microdomains are the crucial intermediary through which integrins regulate Rac. In other words, integrins regulate Rac by regulating these microdomains on membranes where Rac is localized.

In the Science report, del Pozo and his colleagues report that Rac binds preferentially to these microdomains. They also report that when integrins detach from the extracellular matrix, these microdomains are internalized. When del Pozo and his colleagues prevented the microdomains from internalizing, they were able to maintain Rac activity in the cells they studied.

"This [mechanism] could explain how integrins regulate many signaling pathways," says del Pozo.

Significantly, the mechanism could explain why cells need to be attached to the extracellular matrix for the cell cycle to proceed. This mechanism may also have significant consequences for understanding human cancer, since one of the hallmarks of cancer is the independence of integrin-mediated adhesion of the cell cycle.

The article, "Integrins Regulate Rac Targeting by Internalization of Membrane Domains" was authored by Miguel A. del Pozo, Nazilla B. Alderson, William B. Kiosses, Hui-Hsien Chiang, Richard G. W. Anderson, and Martin A. Schwartz, and appears in the February 6, 2004 issue of the journal Science. See



"This [mechanism] could explain how integrins regulate many signaling pathways," says Assistant Professor Miguel del Pozo.