Surprising Finding by VU team Sheds Light on Fibrotic Disease

fibrotic disease
From left, Charles Sanders II, Ph.D., Ambra Pozzi, Ph.D., Sijo Mathew, Ph.D., Roy Zent, M.D., Ph.D., and colleagues have found differences in the structure and function of certain integrins. (photo by Joe Howell)

Integrins are membrane proteins made up of combinations of different “alpha” and “beta” subunits that enable cells throughout the body to interact with their surroundings.

The best-studied integrins, which are found in platelets and other tissues, have beta-3 subunits. Not every integrin has a beta-3 subunit, yet conventional wisdom holds that all integrins act in a manner similar to platelet integrins. But is that really the case?

To find out, researchers at Vanderbilt University School of Medicine studied integrins with beta-1 subunits. To their surprise, they discovered significant differences in the structure and function of these proteins compared to those with beta-3 subunits.

The group’s findings, published recently in the on-line journal eLife, suggest that function may vary significantly depending upon where integrins are located and how they’re made.

“This is just the tip of the iceberg,” said integrin expert Roy Zent, M.D., Ph.D., who partnered with structural biologist Charles Sanders II, Ph.D., and colleagues to conduct the study. “We really don’t know how integrins transmit signals. There probably are big differences between them.”

Understanding how integrins contribute to tissue fibrosis in organs like the liver, lung and kidney could lead to new ways to cure diseases that kill millions of people worldwide, said Zent, the Thomas F. Frist Sr. Professor of Medicine and vice chair of Research in the Department of Medicine.

Sanders said the study began six years ago, and could not have been completed without the persistence of the paper’s first authors, Sijo Mathew, Ph.D., research assistant professor of Medicine, and postdoctoral fellow Zhenwei Lu, Ph.D.

“It’s the collaboration that gives this work distinctive breadth and impact,” said Sanders, who is the Aileen M. Lange and Annie Mary Lyle Professor of Cardiovascular Research, professor of Biochemistry and associate dean for Research in the Basic Sciences. “This is classic Vanderbilt science.”

“By getting me involved in the project, not only could we do these biological, cell-based functional assays that Roy’s lab carries out, but we could also purify the integrins or parts of (them) and do both structural and biophysical characterization of interactions — how the different subunits stick together,” he said.

Sanders said other Vanderbilt scientists have made major contributions to the field of integrin science.

The pioneering work of Samuel Santoro, M.D., Ph.D., and Mary Zutter, Ph.D., for example, helped define the role of platelet integrins in thrombosis. Since the mid-1990s, drugs that target platelet integrins have been used to prevent blood clots.

Santoro is the Dorothy Beryl and Theodore R. Austin Professor of Pathology and chair of the Department of Pathology, Microbiology and Immunology, and Zutter is the Louise B. McGavock Professor in the department.

Another Vanderbilt scientist, Ambra Pozzi, Ph.D., professor of Medicine, demonstrated the major role that integrins play in the pathogenesis of organ fibrosis. Pozzi and Billy Hudson, Ph.D., the Elliott V. Newman Professor of Medicine, also contributed to the current study.