Cell-Type-Specific Activation of PAK2 by Transforming Growth Factor β Independent of Smad2 and Smad3

Abstract

Transforming growth factor β (TGF-β) causes growth arrest in epithelial cells and proliferation and morphological transformation in fibroblasts. Despite the ability of TGF-β to induce various cellular phenotypes, few discernible differences in TGF-β signaling between cell types have been reported, with the only well-characterized pathway (the Smad cascade) seemingly under identical control. We determined that TGF-β receptor signaling activates the STE20 homolog PAK2 in mammalian cells. PAK2 activation occurs in fibroblast but not epithelial cell cultures and is independent of Smad2 and/or Smad3. Furthermore, we show that TGF-β-stimulated PAK2 activity is regulated by Rac1 and Cdc42 and dominant negative PAK2 or morpholino antisense oligonucleotides to PAK2 prevent the morphological alteration observed following TGF-β addition. Thus, PAK2 represents a novel Smad-independent pathway that differentiates TGF-β signaling in fibroblast (growth-stimulated) and epithelial cell (growth-inhibited) cultures.

ACKNOWLEDGMENTS

We thank Rolf Jakobi for the wild-type (pRevTRE-EGFP-γ-PAK) and dominant negative (pRevTRE-EGFP-γ-PAK-K278R) PAK2 plasmids, Azeddine Atfi for the dominant negative (pEGFP-SMAD2-S467A) Smad2 vector, and Jeffrey Field (pCMV5-Rac1^N17 and pCMV5-Cdc42^N17) and Dan Billadeau (pCMV5-RhoA^N19) for dominant negative Rho constructs. Sandra Arline provided excellent technical assistance in the early stages of the project, while Jules Doré provided helpful discussions.

This work was supported by Public Health Service grants GM-54200 and GM-55816 from the National Institute of General Medical Sciences.