title: Role of caveolin-1 in p42/p44 MAP kinase activation and proliferation of human airway smooth muscle.
abstract: Chronic airways diseases, including asthma, are associated with an increased airway smooth muscle (ASM) mass, which may contribute to chronic airway hyperresponsiveness. Increased muscle mass is due, in part, to increased ASM proliferation, although the precise molecular mechanisms for this response are not completely clear. Caveolae, which are abundant in smooth muscle cells, are membrane microdomains where receptors and signaling effectors can be sequestered. We hypothesized that caveolae and caveolin-1 play an important regulatory role in ASM proliferation. Therefore, we investigated their role in p42/p44 MAPK signaling and proliferation using human ASM cell lines. Disruption of caveolae using methyl-beta-cyclodextrin and small interfering (si)RNA-knockdown of caveolin-1 caused spontaneous p42/p44 MAPK activation; additionally, caveolin-1 siRNA induced ASM proliferation in mitogen deficient conditions, suggesting a key role for caveolae and caveolin-1 in maintaining quiescence. Moreover, caveolin-1 accumulates twofold in myocytes induced to a contractile phenotype compared with proliferating ASM cells. Caveolin-1 siRNA failed to increase PDGF-induced p42/p44 MAPK activation and cell proliferation, however, indicating that PDGF stimulation actively reversed the antimitogenic control by caveolin-1. Notably, the PDGF induced loss of antimitogenic control by caveolin-1 coincided with a marked increase in caveolin-1 phosphorylation. Furthermore, the strong association of PDGF receptor-beta with caveolin-1 that exists in quiescent cells was rapidly and markedly reduced with agonist addition. This suggests a dynamic relationship in which mitogen stimulation actively reverses caveolin-1 suppression of p42/p44 MAPK signal transduction. As such, caveolae and caveolin-1 coordinate PDGF receptor signaling, leading to myocyte proliferation, and inhibit constitutive activity of p42/p44 MAPK to sustain cell quiescence.
authors.affiliation: Department of Physiology, University of Manitoba, Winnipeg, Canada. rgosens@mich.ca
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
authors.forename: Gerald L
authors.initials: GL
authors.lastname: Stelmack
authors.forename: Gordon
authors.initials: G
authors.lastname: Dueck
authors.forename: Karol D
authors.initials: KD
authors.lastname: McNeill
authors.forename: Akira
authors.initials: A
authors.lastname: Yamasaki
authors.forename: William T
authors.initials: WT
authors.lastname: Gerthoffer
authors.forename: Helmut
authors.initials: H
authors.lastname: Unruh
authors.forename: Abdelilah Soussi
authors.initials: AS
authors.lastname: Gounni
authors.forename: Johan
authors.initials: J
authors.lastname: Zaagsma
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
mesh_terms: D021941:Caveolae / Q000502:physiology; D051242:Caveolin 1 / Q000494:pharmacology / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D032342:Muscle Cells / Q000502:physiology; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D012137:Respiratory System; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D004268:DNA-Binding Proteins; D010982:Platelet-Derived Growth Factor; D020797:Receptor, Platelet-Derived Growth Factor beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019098:Telomerase