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