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Scientists Discover New Approach to Inhibiting Integrins, with Implications for New Therapeutics for Inflammatory Disease

La Jolla, CA. December 9, 1999 -- Scientists at The Scripps Research Institute (TSRI) in La Jolla, CA., together with their colleagues at Beth Israel Deaconess Medical Center and Harvard Medical School, have discovered a protein-protein interaction important for the function of a class of integrin cell surface receptors that are involved in migration of cells which contribute to chronic inflammation. The work has implications for the development of new compounds capable of blocking interactions within cells necessary for cell migration resulting in treatments for diseases including asthma, multiple sclerosis and rheumatoid arthritis.

"Binding of Paxillin to alpha 4 Integrins Modifies Integrin-Dependent Biological Responses," was published in today's issue of Nature. Its authors are Drs. Shouchun Liu, Darren G. Woodside, David M. Rose, Martin Pfaff, William B. Kiosses, and Mark H. Ginsberg, of The Department of Vascular Biology, The Scripps Research Institute; and Drs. Sheila M. Thomas of the Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School.

The alpha 4 integrins play an important role in embryogenesis, hematopoiesis and the immune response. Scientists believe this is so because they regulate cellular functions differently from other integrins through a particular domain, the cytoplasmic tail. To investigate the mechanism of the effect, the researchers used novel structural analogs of the alpha 4 tail to identify a tight binding partner, the signaling adapter, paxillin.

According to Mark Ginsberg, M.D., Professor, Department of Vascular Biology, "The paxillin-alpha 4 interaction is one of the tightest of the known protein-protein interactions of integrin cytoplasmic domains. This is suggestive of potential targets for therapeutics." The paper notes that the tight association of paxillin with the alpha 4 tail leads to distinct biochemical and biological responses to integrin-mediated cell adhesion.

While extracellular inhibitors for of this class of integrins are under development for asthma and multiple sclerosis, this work identifies a new target to inhibit the receptor. Ginsberg continues, "Inhibition through this alternative mechanism offers a potential opportunity for development of compounds with a distinct therapeutic profiles."

This study was funded by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Heart, Lung and Blood Institute of the National Institutes of Health.

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