Role of caveolin-1 in p42/p44 MAP kinase activation and proliferation of human airway smooth muscle

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 291; no. 3; pp. L523 - L534
• Main Authors: Gosens, Reinoud, Stelmack, Gerald L, Dueck, Gordon, McNeill, Karol D, Yamasaki, Akira, Gerthoffer, William T, Unruh, Helmut, Gounni, Abdelilah Soussi, Zaagsma, Johan, Halayko, Andrew J
• Format: Journal Article
• Language: English
• Published: United States 01.09.2006
• Subjects: Caveolae - physiology; Caveolin 1 - pharmacology; Caveolin 1 - physiology; Cell Line; Cell Proliferation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enzyme Activation; Humans; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Muscle Cells - physiology; Muscle, Smooth - cytology; Muscle, Smooth - metabolism; Phosphorylation; Platelet-Derived Growth Factor; Receptor, Platelet-Derived Growth Factor beta - metabolism; Respiratory System; Signal Transduction; Telomerase - genetics; Telomerase - metabolism
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00013.2006

1 Departments of Physiology and Internal Medicine, University of Manitoba, Winnipeg, Manitoba; 2 Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada; 3 Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; 4 Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada; and 5 Section of Thoracic Surgery, and 6 Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada Submitted 10 January 2006 ; accepted in final form 13 April 2006 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- -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- 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. airway remodeling; hyperplasia; airway smooth muscle phenotype; platelet-derived growth factor receptor- ; asthma Address for reprint requests and other correspondence: R. Gosens, Dept. of Physiology, Univ. of Manitoba, 715 McDermot Ave., Rm. 547, John Buhler Research Centre, Winnipeg, Manitoba, Canada R3E 3P4 (e-mail: rgosens{at}mich.ca )