A central paradox in transforming growth factor beta (TGF-B) 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-B has in both normal growth control and various proliferative disorders, addressing that issue is fundamental if we hope to develop specific intervention strategies. To that end, during the previous funding cycle we have determined that p21-activated kinase 2 (PAK2) represents a new cell type specific signaling pathway stimulated by TGF-B. PAKs were first identified as effectors of Rho GTPases and have been implicated as regulators of actin reorganization, cell motility, apoptosis, gene transcription, and oncogenesis. In this competing renewal we wish to extend these findings and test the general hypothesis that PAK2 activation defines a critical branchpoint(s) in distinguishing mesenchymal from epithelial cell responses to TGF-B. This hypothesis will be addressed through a variety of biochemical, biological, and genetic approaches. First, we will determine the role of Ras and Rho family members in TGF-B-stimulated PAK2 activation. Second, the function of PI3K and its spatiotemporal relation to Ras and Rho GTPases in PAK2 signaling will be defined. Finally, we will characterize the downstream mediators through which TGF-B-stimulated PAK2 activity regulates MAPK activation. As these studies represent (i) a new Smad-independent signaling pathway for TGF-B; and (ii) the first demonstration of cell type specific TGF-B signaling, answers to these questions are critical if the mechanisms controlling the various biological responses to TGF-B are to be elucidated. ? ? ?
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