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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/L1348    most recent 00346.2007v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Gosens, R. Articles by Halayko, A. J. Search for Related Content PubMed PubMed Citation Articles by Gosens, R. Articles by Halayko, A. J.

Cooperative regulation of GSK-3 by muscarinic and PDGF receptors is associated with airway myocyte proliferation

¹Departments of Physiology and Internal Medicine, University of Manitoba, Winnipeg; ²Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg; ³Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; ⁴Flow Cytometry Laboratory, University of Manitoba, Winnipeg; ⁵Escola Superior de Tecnologia da Saúde de Lisbon, Lisbon, Portugal; ⁶Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada; ⁷Section of Thoracic Surgery, University of Manitoba, Winnipeg, Manitoba, Canada

Submitted 23 August 2007 ; accepted in final form 8 September 2007

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 promitogenic signaling pathways in its unphosphorylated form, is cooperatively inhibited by 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 also were observed on PDGF-induced retinoblastoma protein (Rb) phosphorylation and cell proliferation. Suppression of GSK-3 inhibitory function using SB 216763 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, since it was abolished by GF 109203X and Gö 6976; 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.

asthma; airway hyperresponsiveness; cell cycle; G protein-coupled receptor; airway remodeling

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