GSK-3/beta-catenin signaling axis in airway smooth muscle: role in mitogenic signaling.
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.
Nunes
Raquel O
RO
Deptartment of Molecular Pharmacology, Univ. of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Schmidt
Martina
M
Dueck
Gordon
G
Baarsma
Hoeke
H
Halayko
Andrew J
AJ
Kerstjens
Huib A M
HA
Meurs
Herman
H
Gosens
Reinoud
R
D001980:Bronchi; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
C495270:CTNNB1 protein, human; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3