Role of caveolin-1 in p42/p44 MAP kinase activation and proliferation of human airway smooth muscle
Role of caveolin-1 in p42/p44 MAP kinase activation and proliferation of human airway smooth muscle
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DOI：
10.1152/ajplung.00013.2006
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发表时间：
2006-09-01
影响因子：
4.9
通讯作者：
Halayko, Andrew J.
中科院分区：
文献类型：
--
作者：
Gosens, Reinoud;Stelmack, Gerald L.;Halayko, Andrew J.
慢性气道疾病，包括哮喘，与气道平滑肌（ASM）质量增加有关，这可能导致慢性气道高反应性。肌肉质量的增加部分是由于ASM增殖的增加，尽管这种反应的确切分子机制尚不完全清楚。平滑肌细胞中大量存在的小泡是受体和信号效应器可以隔离的膜微结构域。我们假设小泡和小泡蛋白-1在ASM增殖中起重要的调节作用。因此，我们利用人ASM细胞系研究了它们在p42/p44 MAPK信号传导和增殖中的作用。甲基- β -环糊精破坏小泡和小泡蛋白-1的小干扰（si） rna敲低引起p42/p44 MAPK自发激活；此外，在有丝分裂原缺乏的情况下，小洞蛋白-1 siRNA诱导ASM增殖，这表明小洞蛋白和小洞蛋白-1在维持休眠中起着关键作用。此外，在收缩型肌细胞中，小窝蛋白-1的积累是增生型肌细胞的两倍。然而，Caveolin-1 siRNA未能增加PDGF诱导的p42/p44 MAPK激活和细胞增殖，这表明PDGF刺激积极逆转了Caveolin-1的抗噬控制。值得注意的是，PDGF诱导的小洞蛋白-1抗丝原性控制的丧失与小洞蛋白-1磷酸化的显著增加相一致。此外，静止细胞中存在的PDGF受体- β与caveolin-1的强关联随着激动剂的加入而迅速显著降低。这表明有丝分裂原刺激积极逆转小泡蛋白-1抑制p42/p44 MAPK信号转导的动态关系。因此，小泡和小泡蛋白- 1协调PDGF受体信号传导，导致肌细胞增殖，并抑制p42/p44 MAPK的组成活性以维持细胞静止。
Chronic airways diseases, including asthma, are associated with an increased airway smooth muscle (ASM) mass, which may contribute to chronic airway hyperrespon-siveness. 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.