Vital molecular step in cell migration

A vital molecular step in cell migration, the movement of cells within the body during growth, tissue repair and the body's immune response to invading pathogens, has been demonstrated by researchers in the University of California, San Diego (UCSD) School of Medicine.

Published in the March 27 online edition of Nature Cell Biology and the journal's upcoming April print edition, the study describes how a the interaction of alpha4 integrin adhesion receptor with a protein called paxillin creates directional movement of a cell by inhibiting a protein called Rac.

"Understanding how this protein contributes to directional movement of a cell provides a new insight into cell migration and ultimately could lead to therapeutic interventions in autoimmune diseases such as multiple sclerosis and Crohn's disease," said the paper's first author Naoyuki Nishiya, Ph.D., a postgraduate researcher in the lab of senior author Mark Ginsberg, M.D., UCSD professor of medicine. "Since cell migration plays an important role in the immune response, as leukocytes move toward targets, a therapy that stops that movement could potentially help in autoimmune disorders where the body's immune system incorrectly attacks the body's own tissue."

From the genesis of human life to birth and beyond, cell migration is a complex, extremely important process that is not completely understood by researchers. In order to move, a cell must be polarized so that the molecular processes at the front end and back end are different, leading only to forward movement. One of the first steps in cell migration is the initiation of activity by Rac that extends protrusions out of the cell. These protrusions serve as tractor sites for migration as the cell moves toward its intended target. If Rac were active throughout the cell, it would extend protrusions in all directions, in essence keeping the cell in one place.

Until now, researchers have had limited understanding of the molecular mechanism that inhibits Rac activity in the back of the cell, to maintain directional movement. In laboratory experiments with human and animal cells, the UCSD team discovered that the alpha4 integrin recruits enzymes that block Rac activity only at the rear of a crawling cell.

The scientists noted that alpha4 integrins are widely expressed in neural crest cells, immune system leukocytes (such as T cells), striated and smooth muscle, and neurons. For this reason, they believe the mechanism used by alpha4 integrins to localize Rac activity may participate in a wide variety of cell migratory and pathfinding events.

In addition to Nishiya and Ginsberg, additional authors were William B. Kiosses, Ph.D., The Scripps Research Institute, La Jolla, California; and Jaewon Han, Ph.D., UCSD Department of Medicine. The study was funded by the National Institutes of Health.