It is proposed to define molecular events involved in cellular activation by type Beta transforming growth factor (TGfBeta). TGFBeta is a hormonally active polypeptide protein in blood platelets and in other normal and transformed sources. The cellular actions of TGFBeta include induction of the transformed phenotype in mesenchimal cells, inhibition of proliferation in epithelial and carcinoma cells, and control of differentiation of other cell types. We have identified high-affinity cellular receptors for TGFBeta and accumulated information on the functional and structural properties of this receptor type. However, the molecular basis for the cellular actions of TGFBeta is unknown. We are addressing this problem in two complementary ways. First, we propose to purify this receptor molecule from sources that provide working amounts of it, using specific affinity-chromatography steps. Purified receptor preparations will be used to validate the disulfide-linked subunit structure that we have proposed for the TGFBeta receptor based on receptor affinity-labeling studies. The structural and ligand binding properties of the purified receptor will be characterized in detail. We will seek to raise monoclonal antibodies against the TGFBeta receptor. Antibodies will be used to further characterize the structure and biochemistry of TGFBeta receptors. The second way in which we are studying TGFBeta action is by identifying molecular events induced by TGFBeta and potentially involved in its varied cellular actions. We are examining the extracellular matrix (EM) as a potentially key target for TGFBeta because, i) alterations of the EM can modulate the proliferation and differentiation of many cell types, ii) the EM is critically involved in the process of wound healing, a process which platelet TGFBeta is physiologically targeted for, and iii) we find that TGFBeta activates sharply the production and incorporation of fibronectin, a central component of the EM. We propose to examine in detail the TGFBeta receptor-mediated stimulation of fibronectin synthesis in fibroblasts and other cell types at the protein and mRNA levels. It is expected that the double approach at the receptor/postreceptor levels that we propose will generate information critical for understanding the key molecular events involved in TGFBeta action.
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