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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/L1110    most recent 00500.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Nunes, R. O. Articles by Gosens, R. PubMed PubMed Citation Articles by Nunes, R. O. Articles by Gosens, R.

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