Transforming growth factor Beta (TGF-Beta) is an important cytokine that regulates cell proliferation, cell migration, extracellular matrix synthesis and inflammatory responses in most cell types of the body. TGF-Beta-binding proteins in the extracellular matrix and at cell surfaces regulate the access of TGF-Beta to its signaling receptors in that some of them appear to facilitate receptors binding while others inhibit it. The binding proteins also localize the TGF-Beta effects to the area of its production--this appears to be a general principle with growth factors; most of them bind to extracellular matrices and cell surfaces and as a consequence affect cells in geometries defined by tissue architecture.
The aim of the work proposed here is to identify and characterize proteins that bind TGF-Beta into the extracellular matrix. We have previously shown that the small proteogylcans in the decorin family bind TGF-Beta and can neutralize its biological activity, and others have demonstrated TFG-Beta binding to other matrix proteins. The 60 kDa protein binds to glycosaminoglycans and, therefore, appears to mediate binding between TGF-Beta and proteoglycans in the matrix and at cell surfaces. We propose to characterize this and other matrix proteins, and their ability to bind TGF while in the matrix environment, by isolating cDNA clones (when they are novel proteins) and by determining their effect on the binding of TGF-Beta to the TGF-Beta receptors, by identifying their binding sites in TGF-beta and by studying their tissue distribution in relation to that of TGF-Beta. Since TGF-Beta and this receptors are expressed nearly ubiquitously in various cell types and tissues, cell type-specific binding proteins such as the ones we propose to study are likely to play an important role in modulating the activities of this growth factor. Thus, our study will contribute to the understanding of this important factor and may point to new ways of controlling its activity in disease.
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