Cellular proliferation is controlled by the integrated action of stimulatory and inhibitory growth factors. Transforming growth factor beta (TGF-beta) is unique in that regard since depending upon the cellular context it can either stimulate or inhibit cell growth. In general, mesenchymal-derived cells are growth stimulated while most other cell types are inhibited. It is presently unknown how 1 growth factor, binding to the same receptor species, can elicit such distinct phenotypes. The pivotal role which TGF-beta plays in modulating a number of biological activities makes it critical to identify potential targets through which TGF-beta actions are regulated. During the previous funding cycle we have determined that receptor endocytic activity is differentially modulated in mesenchymal and epithelial cell lines and that major determinants of TGF-beta receptor (TGF-betaR) internalization and signaling are the type II receptor kinase and a novel element in the type I receptor, respectively. We wish to extend these findings and test the general hypothesis that the cellular response to TGF-beta is controlled by the integrated activities of the endocytic and signaling machinery. This hypothesis will be addressed through a variety of approaches. First, we will characterize cellular proteins which regulate the initial membrane response to TGF- betaR oligomerization. Next, we will determine the function of a previously undefined element in the type I TGF-betaR in controlling downstream receptor signaling. Finally, we will identify mammalian TGF-beta signaling intermediaries using genetic analysis of yeast. Considering the importance of TGF- beta in various proliferative disorders, answers to these type of questions are critical if we hope to develop specific (and novel) intervention strategies.
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