(revised by applicant): In the prostate, transforming growth factor-beta (TGFb) promotes growth arrest and apoptosis of epithelial cells and can either suppress or promotes tumor growth. The mechanisms by which TGFb mediates these processes are under intense investigation. TGFbl signals through promoting the binding and activation of the TGFb type I receptor (TbRI) by TbRII. Activated TbRI phosphorylates Smads 2 and 3, which promotes both their and Smad4's entry in the nucleus, where they directly or indirectly regulate transcription. A current dogma in this field is that TbRII signals only through activation of TbRI. Another dogma is that Smads are the critical trigger of virtually all TGF-b responses including growth arrest and apoptosis. However, accumulating evidence is strengthening the notion that TGFb activates a number of other kinases (i.e., MAPKs) independent of Smads. Despite these advances, nothing is known about how TbRI and TbRII activate such Smad-independent signal. We propose to test the following hypothesis: TbRII is critical to TGFb signal transduction not only through activating TbRI, that activates receptor Smads, but also by mediation of Smad-independent TGFb signals. We will test this hypothesis in prostatic epithelial cell lines by studying: i) the role of EGF in regulating TGFb responses, ii) the structural/functional basis of TbRI and TbRII and the role of Smads and MAPKs in the activation of AP-1, and iii) regulation of growth inhibition by constitutively activated Smads.
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