De novo synthesis of {beta}-catenin via H-Ras and MEK regulates airway smooth muscle growth

• Published in: The FASEB journal 2010-03, Vol.24 (3), p.757-768
• Main Authors: Gosens, Reinoud, Baarsma, Hoeke A, Heijink, Irene H, Oenema, Tjitske A, Halayko, Andrew J, Meurs, Herman, Schmidt, Martina
• Format: Article
• Language: English
• Subjects: beta Catenin - genetics; beta Catenin - metabolism; Blotting, Western; Bronchi - cytology; Butadienes - pharmacology; Cell Line; Cell Proliferation; Cells, Cultured; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Genes, ras - genetics; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - physiology; Humans; Immunohistochemistry; Immunoprecipitation; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - physiology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Nitriles - pharmacology; Polymerase Chain Reaction; Transforming Growth Factor beta - pharmacology
• ISSN: 1530-6860
• DOI: 10.1096/fj.09-136325

beta-Catenin is a component of adherens junctions that also acts as a transcriptional coactivator when expressed in the nucleus. Growth factors are believed to regulate the nuclear expression of beta-catenin via inactivation of glycogen synthase kinase 3 (GSK-3) by phosphorylation, resulting in increased beta-catenin protein stability. Here, we report on a novel pathway that regulates the expression and nuclear presence of beta-catenin. In proliferating human airway smooth muscle cells, we observed increased expression of beta-catenin, which was required for proliferation. Interestingly, increased beta-catenin expression was accompanied by an increase in beta-catenin mRNA and was independent of beta-catenin liberation from the plasma membrane, suggesting a role for de novo synthesis. This was confirmed using actinomycin D and cycloheximide, which abrogated the induction and nuclear localization of beta-catenin protein. GSK-3 inhibition using SB216763 failed to regulate beta-catenin mRNA. However, expression of dominant negative H-Ras or pharmacological inhibition of MEK reduced serum and TGF-beta-induced beta-catenin mRNA and protein. Collectively, these data indicate that beta-catenin is an important signaling intermediate in airway smooth muscle growth and that its cellular accumulation and nuclear localization require de novo protein synthesis effected, in part, via H-Ras and MEK.-Gosens, R., Baarsma, H. A., Heijink, I. H., Oenema, T. A., Halayko, A. J., Meurs, H., Schmidt, M. De novo synthesis of beta-catenin via H-Ras and MEK regulates airway smooth muscle growth.