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GSK-3/β-catenin signaling axis in airway smooth muscle: role in mitogenic signaling

¹Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; ²Escola Superior de Tecnologia da Saúde de Lisboa, Lisbon, Portugal; ³Departments of Physiology and Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; and ⁴Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Submitted 5 December 2007 ; accepted in final form 25 March 2008

β-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 β-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 β-catenin, which was localized primarily to the plasma membrane in quiescent cells. Treatment of airway smooth muscle cells with PDGF or FBS induced sustained phosphorylation of glycogen synthase kinase-3 (GSK-3), a negative regulator in its unphosphorylated form that promotes β-catenin degradation. GSK-3 phosphorylation was also increased in airway smooth muscle cells with a proliferative phenotype compared with 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 β-catenin and activated promitogenic signaling in airway smooth muscle, including the phosphorylation of retinoblastoma protein, DNA synthesis ([³H]thymidine incorporation), and cell proliferation. Importantly, small interfering RNA knockdown of β-catenin strongly reduced retinoblastoma protein phosphorylation, [³H]thymidine incorporation, and cell proliferation induced by PDGF and FBS. Collectively, these data reveal the existence of a GSK-3/β-catenin signaling axis in airway smooth muscle that is regulated by growth factors and of central importance to mitogenic signaling.

airway remodeling; asthma; proliferation; growth factor

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