Transforming growth factor-β (TGF-β) stimulates different responses depending on cell type; for example, epithelial cells undergo growth arrest in response to TGF-β, whereas fibroblasts undergo morphological changes and proliferate. Wilkes et al. determined that p21-activated kinase 2 (PAK2) is one downstream signaling component that is selectively activated in fibroblasts. The kinase activity of PAK2 was stimulated by TGF-β in all cultured fibroblast cells tested but was not stimulated in any of the epithelial cells treated with TGF-β. Surprisingly, neither Smad2 nor Smad 3, the mediators of the canonical TGF-β pathway, were required for PAK2 activation in fibroblasts. Full stimulation of PAK2 by TGF-β required guanosine triphosphate (GTP) loading of the GTPases Cdc42 and Rac1, which interacted directly with PAK2 in TGF-β-stimulated fibroblasts. This interaction was not observed in epithelial cells. Finally, the TGF-β-stimulated morphological changes and proliferative response of fibroblasts were blocked by transfection of dominant-negative PAK2 or antisense treatments to decrease PAK2 protein. Thus, cell-specific responses can arise from a noncanonical TGF-β pathway that does not involve Smads and that regulates the cytoskeleton through the stimulation of PAK2.
M. C. Wilkes, S. J. Murphy, N. Garamszegi, E. B. Leof, Cell-type-specific activation of PAK2 by transforming growth factor β independent of Smad2 and Smad3. Mol. Cell. Biol. 23, 8878-8889 (2003). [Abstract] [Full Text]