Submitted on December 5, 2007
Accepted on March 25, 2008
The GSK-3/
-catenin Signaling Axis in Airway Smooth Muscle: Role in Mitogenic Signaling
Raquel Oliveira Nunes1, Martina Schmidt2, Gordon Dueck3, Hoeke Baarsma4, Andrew John Halayko3, Huib A.M. Kerstjens5, Herman Meurs2, and Reinoud Gosens2*
1 Department of Molecular Pharmacology, University of Groningen, Groningen, Netherlands; Escola Superior de Tecnologia da Saude de Lisboa , Lisbon, Portugal
2 Department of Molecular Pharmacology, University of Groningen, Groningen, Netherlands
3 Departments of Physiology & Internal Medicine, University of Manitoba, Winnipeg, Canada
4 Molecular Pharmacology, University of Groningen, Netherlands
5 Pulmonary Medicine, Groningen University Medical Center, Groningen, Netherlands
* To whom correspondence should be addressed. E-mail: r.gosens{at}rug.nl.
-Catenin plays a dual role in cellular signaling by stabilizing cadherin mediated cell-cell contact and by regulating gene transcription associated with cell cycle progression. Nonetheless, its presence and function in airway smooth muscle have not been determined. We hypothesized a central role for -catenin in mitogenic signaling in airway smooth muscle in response to growth factor stimulation. Immunocytochemical and biochemical analysis revealed that human airway smooth muscle cells indeed express abundant -catenin, which was localized primarily to the plasma membrane in quiescent cells. Treatment of airway smooth muscle cells with platelet-derived growth factor (PDGF) or fetal bovine serum (FBS) induced sustained phosphorylation of glycogen synthase kinase-3 (GSK-3), a negative regulator of -catenin in its unphosphorylated form that promotes -catenin degradation . GSK-3 phosphorylation was also increased in airway smooth muscle cells with a proliferative phenotype compared to quiescent airway smooth muscle cells with a mature phenotype. Parallel with the increase in GSK-3 phosphorylation, growth factor treatment induced an increased expression and nuclear presence of -catenin and activated pro-mitogenic signaling in airway smooth muscle including the phosphorylation of retinoblastoma (Rb) protein, DNA synthesis ([3H]thymidine incorporation) and cell proliferation. Importantly, siRNA knockdown of -catenin strongly reduced Rb protein phosphorylation, [3H]thymidine incorporation and cell proliferation induced by PDGF and FBS. Collectively, these data reveal the existence of a GSK-3/-catenin signaling axis in airway smooth muscle that is regulated by growth factors and of central importance to mitogenic signaling.
