A central paradox in transforming growth factor beta (TGF-?) biology is how the same growth factor can induce such divergent responses as growth stimulation (i.e., mesenchymal cells) and growth inhibition (i.e., epithelial cells)? Considering the pivotal role TGF-? has in a number of normal and pathological conditions, addressing that issue is fundamental if we hope to develop specific intervention strategies. To that end, we have been investigating the general hypothesis that TGF-? stimulates cell type-specific signaling pathways as a means to regulate these phenotypes. One target with a critical role in coordinating the profibrogenic (i.e., mesenchymal), in contrast to the growth inhibitory (i.e., epithelial), cellular response to TGF-? is PI3K. During the previous funding cycle we have shown that PI3K represents a branchpoint in Smad-independent TGF-? signaling such that one arm leads to activation of Pak2 and c-Abl, while the other is coupled to Akt and mTOR. As this former finding has led to a multi-center Phase II clinical trial testing the efficacy of imatinib mesylate vs. placebo in the treatment of idiopathic pulmonary fibrosis, we will extend these concepts in the competing renewal using a variety of biochemical, biological, and morphologic approaches. First, we will determine the mechanism(s) by which TGF-? activation of mTOR stimulates stromal cell proliferation. It is proposed that greater efficacy and lower toxicity can be obtained in models of TGF-? driven tissue fibrosis by inhibiting both Pak2/c-Abl and Akt/mTOR branches downstream of PI3K. Second, the role of guanine nucleotide exchange factor (GEF) phosphorylation and receptor association in directing TGF-? target specificity and receptor activation will be defined. Third, a candidate protein has been identified which regulates fibroblast-specific TGF-? signaling, experiments are proposed to determine the mechanism(s) which prevents or promotes activation of these pathways in epithelial and mesenchymal cells, respectively. Answers to these questions are critical if the processes mediating cell type-specific TGF-? signaling are to be elucidated. Relevance to public health (lay language): TGF-? is a protein which can be either helpful or harmful to human health. While its ability to stimulate cell growth is important for normal wound healing, when unchecked the function of many organs can be disrupted by scar (i.e., fibrosis) formation. The proposed studies will identify/characterize targets which can be used to either increase or decrease this response.
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