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1 Physiology and Internal Medicine, University of Manitoba, Winnipeg, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Canada; Molecular Pharmacology, University of Groningen, Groningen, Netherlands
2 Physiology and Internal Medicine, University of Manitoba, Winnipeg, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Canada
3 Pharmacology, University of Nevada School of Medicine, Reno, United States
4 Section of Thoracic Surgery, University of Manitoba, Winnipeg, Canada
5 Immunology, University of Manitoba, Winnipeg, Canada
6 Molecular Pharmacology, University of Groningen, Groningen, Netherlands
* To whom correspondence should be addressed. E-mail: rgosens{at}mich.ca.
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, though 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-
-cyclodextrin and siRNA-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 two-fold in myocytes induced to a contractile phenotype compared to 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 anti-mitogenic control by caveolin-1. Notably, the PDGF induced loss of anti-mitogenic control by caveolin-1 coincided with a marked increase in caveolin-1 phosphorylation. Furthermore the strong association of PDGFR with caveolin-1 that exists in quiescent cells was rapidly and markedly reduced upon 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.
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