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1 Departments of Physiology & Internal Medicine, University of Manitoba, Winnipeg, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Canada; Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, Groningen, 9713 AV, Netherlands
2 Departments of Physiology & Internal Medicine, University of Manitoba, Winnipeg, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Canada
3 Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Canada; Flow Cytometry Laboratory, University of Manitoba, Winnipeg, Canada
4 Molecular Pharmacology, University of Groningen, Groningen, Netherlands
5 Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada, United States
6 Section of Thoracic Surgery, University of Manitoba, Winnipeg, Canada
* To whom correspondence should be addressed. E-mail: r.gosens{at}rug.nl.
Muscarinic receptors and platelet-derived growth factor (PDGF) receptors synergistically induce proliferation of airway smooth muscle (ASM), but the pathways that regulate these effects are not yet completely identified. We hypothesized that glycogen synthase kinase-3 (GSK-3), a kinase that represses several pro-mitogenic signaling pathways in its unphosphorylated form, is cooperatively inhibited by platelet-derived growth factor (PDGF) and muscarinic receptors in immortalized human ASM cell lines. PDGF or methacholine alone induced rapid GSK-3 phosphorylation. This phosphorylation was sustained only for PDGF; however, methacholine potentiated PDGF-induced, sustained GSK-3 phosphorylation. Synergistic effects of methacholine were also observed on PDGF-induced retinoblastoma protein (Rb) phosphorylation and cell proliferation. Suppression of GSK-3 inhibitory function using SB216763 also augmented PDGF-induced Rb phosphorylation and cell cycle progression; this synergy was similar in magnitude to that seen for methacholine with PDGF. GSK-3 phosphorylation induced by methacholine required PKC, as it was abolished by GF109203X and Go6976; however, inhibition of PKC had no effect on cell responses to PDGF. PKC inhibition also specifically abolished the synergistic effect of methacholine on PDGF-induced GSK-3 phosphorylation and cell proliferation. Collectively, these results show that GSK-3 plays a key repressive role in ASM cell proliferation. Moreover, muscarinic receptors mediate PKC-dependent GSK-3 inhibition, and this appears to be a primary mechanism underpinning augmentation of PDGF-induced cell growth.
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