Wilkes Mark C, Murphy Stephen J, Garamszegi Nandor, Leof Edward B
Department of Biochemistry and Molecular Biology, Thoracic Diseases Research Unit, and Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Mol Cell Biol. 2003 Dec;23(23):8878-89. doi: 10.1128/MCB.23.23.8878-8889.2003.
Transforming growth factor beta (TGF-beta) causes growth arrest in epithelial cells and proliferation and morphological transformation in fibroblasts. Despite the ability of TGF-beta to induce various cellular phenotypes, few discernible differences in TGF-beta signaling between cell types have been reported, with the only well-characterized pathway (the Smad cascade) seemingly under identical control. We determined that TGF-beta 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-beta-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-beta addition. Thus, PAK2 represents a novel Smad-independent pathway that differentiates TGF-beta signaling in fibroblast (growth-stimulated) and epithelial cell (growth-inhibited) cultures.
转化生长因子β（TGF-β）可导致上皮细胞生长停滞，成纤维细胞增殖及形态转变。尽管TGF-β有诱导多种细胞表型的能力，但据报道，不同细胞类型间TGF-β信号传导几乎没有明显差异，唯一特征明确的途径（Smad级联反应）似乎受相同调控。我们确定TGF-β受体信号传导可激活哺乳动物细胞中的STE20同源物PAK2。PAK2激活发生在成纤维细胞培养物中，而非上皮细胞培养物中，且不依赖于Smad2和/或Smad3。此外，我们发现TGF-β刺激的PAK2活性受Rac1和Cdc42调控，显性负性PAK2或PAK2的吗啉代反义寡核苷酸可阻止添加TGF-β后观察到的形态改变。因此，PAK2代表一种新的不依赖Smad的途径，可区分成纤维细胞（生长受刺激）和上皮细胞（生长受抑制）培养物中的TGF-β信号传导。
