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

2008; American Physical Society; Volume: 294; Issue: 6 Linguagem: Inglês

10.1152/ajplung.00500.2007

1522-1504

Raquel O. Nunes, Martina Schmidt, Gordon Dueck, Hoeke A. Baarsma, Andrew J. Halayko, Huib A.M. Kerstjens, Herman Meurs, Reinoud Gosens,

Hedgehog Signaling Pathway Studies

Beta-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 beta-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 beta-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 beta-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 beta-catenin and activated promitogenic signaling in airway smooth muscle, including the phosphorylation of retinoblastoma protein, DNA synthesis ([(3)H]thymidine incorporation), and cell proliferation. Importantly, small interfering RNA knockdown of beta-catenin strongly reduced retinoblastoma protein phosphorylation, [(3)H]thymidine incorporation, and cell proliferation induced by PDGF and FBS. Collectively, these data reveal the existence of a GSK-3/beta-catenin signaling axis in airway smooth muscle that is regulated by growth factors and of central importance to mitogenic signaling.