Transforming growth factor beta (TGFbeta) is a prototype of a large family of secreted polypeptide growth factors which plays important roles in cellular growth, development and differentiation. TGFbeta inhibits the differentiation of certain cells of mesenchymal origin, induces the differentiation of others, and potently inhibits proliferation of various types of epithelial cells. It is this latter activity of maintaining cells in a repressed growth state that has led to the hypothesis that loss of a growth inhibitory response to TGFbeta may lead to uncontrolled growth and ultimately initiate the carcinogenic process. Members of the TGFbeta family signal through the serine-threonine kinase class of receptors which in turn modulate the Smad family of signaling molecules which are critical in transmitting the TGFbeta signal from the cell surface into the nucleus. Emerging evidence indicates that, while the Smad proteins are central to TGFbeta signaling, other signaling molecules and pathways are necessary for efficient signaling. We have previously developed a genetic system for the analysis of TGFbeta signaling consisting of a set of recessive TGFbeta-mutant cell lines which could be functionally complemented to identify signaling molecules. Using this strategy, we have identified an adaptor molecule, Dab2, which we hypothesize couples the TGFbeta receptors to the Smad complex, as well as other signaling pathways. In this application, we propose to characterize the role of this adaptor molecule in TGFbeta signaling, and to identify and characterize other signaling molecules involved in TGFbeta signal transduction. In this proposal we wish to characterize the interaction between Dab2 and Smad2, to determine the role of Dab2 in the regulation of the MAPK pathway by TGFbeta, and to isolate and characterize cDNAs which complement TGFbeta signaling mutant cell lines. Identification and functional characterization of these interactions and proteins will not only permit a greater understanding of TGFbeta action, but suggest potential targets for therapeutic intervention in cancer.
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