Src is necessary and sufficient for human airway smooth muscle cell proliferation and migration

Abstract

Airway smooth muscle (ASM) hypertrophy and hyperplasia, important pathological features in chronic severe asthma, likely contribute to irreversible airflow obstruction. Despite considerable research effort, the precise cellular mechanisms that modulate ASM growth remain unknown. Src, a nonreceptor tyrosine kinase proto-oncogene, reportedly modulates cell proliferative responses to growth factors, contractile agonists, and inflammatory mediators. Here, we show that Src activation is required for human ASM mitogenesis and motility. Platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and thrombin induce rapid activation of Src, and inhibition of Src induces a concentration-dependent abrogation of PDGF-, EGF-, and thrombin-induced ASM cell proliferation. Src immunoprecipitates had associated phosphatidylinositol 3-kinase, or PI3K, activation in response to PDGF and thrombin but not EGF. Further, Src activation is both necessary and sufficient for the stimulation of DNA synthesis as demonstrated by dominant negative Src inhibition of PDGF-, EGF-, and thrombin-induced DNA synthesis. Human ASM cell migration was also attenuated by transfection of cells with dominant negative Src. Further, expression of constitutively active Src promoted cell migration. Collectively, these data demonstrate that Src modulates human ASM cell proliferation and migration, suggesting that Src may play an important role in promoting ASM cell growth and migration that occur in airway remodeling found in asthma and chronic obstructive pulmonary disease, or COPD.