Abstract
BackgroundAirway smooth muscle contraction is critical for maintenance of appropriate airway tone, and has been implicated in asthma pathogenesis. Smooth muscle contraction requires an “engine” (myosin activation) and a “transmission system” (actin cytoskeletal remodeling). However, the mechanisms that control actin remodeling in smooth muscle are not fully elucidated. The adapter protein Crk-associated substrate (CAS) regulates actin dynamics and the contraction in smooth muscle. In addition, profilin-1 (Pfn-1) and Abelson tyrosine kinase (c-Abl) are also involved in smooth muscle contraction. The interplays among CAS, Pfn-1 and c-Abl in smooth muscle have not been previously investigated.MethodsThe association of CAS with Pfn-1 in mouse tracheal rings was evaluated by co-immunoprecipitation. Tracheal rings from c-Abl conditional knockout mice were used to assess the roles of c-Abl in the protein-protein interaction and smooth muscle contraction. Decoy peptides were utilized to evaluate the importance of CAS/Pfn-1 coupling in smooth muscle contraction.ResultsStimulation with acetylcholine (ACh) increased the interaction of CAS with Pfn-1 in smooth muscle, which was regulated by CAS tyrosine phosphorylation and c-Abl. The CAS/Pfn-1 coupling was also modified by the phosphorylation of cortactin (a protein implicated in Pfn-1 activation). In addition, ACh activation promoted the spatial redistribution of CAS and Pfn-1 in smooth muscle cells, which was reduced by c-Abl knockdown. Inhibition of CAS/Pfn-1 interaction by a decoy peptide attenuated the ACh-induced actin polymerization and contraction without affecting myosin light chain phosphorylation. Furthermore, treatment with the Src inhibitor PP2 and the actin polymerization inhibitor latrunculin A attenuated the ACh-induced c-Abl tyrosine phosphorylation (an indication of c-Abl activation).ConclusionsOur results suggest a novel activation loop in airway smooth muscle: c-Abl promotes the CAS/Pfn-1 coupling and actin polymerization, which conversely facilitates c-Abl activation. The positive feedback may render c-Abl in active state after contractile stimulation.
Highlights
Airway smooth muscle contraction is critical for maintenance of appropriate airway tone, and has been implicated in asthma pathogenesis
Contractile activation increases the coupling of Crk-associated substrate (CAS) with Pfn-1 in smooth muscle CAS and Pfn-1 are involved in the regulation of actin reorganization and smooth muscle contraction [4, 6, 22, 37, 38]
The results suggest that contractile activation promotes the interaction of CAS with Pfn-1 in smooth muscle
Summary
Airway smooth muscle contraction is critical for maintenance of appropriate airway tone, and has been implicated in asthma pathogenesis. Smooth muscle contraction requires an “engine” (myosin activation) and a “transmission system” (actin cytoskeletal remodeling). The adapter protein Crk-associated substrate (CAS) regulates actin dynamics and the contraction in smooth muscle. Myosin light chain undergoes phosphorylation at Ser-19, which initiates sliding of contractile filaments and smooth muscle contraction [1, 2]. Actin filaments of smooth muscle connect with the extracellular matrix via the integrin-associated complex [3,4,5,6]. Myosin can be viewed as an “engine” and the actin cytoskeleton as a “transmission system” for smooth muscle contraction [4, 11,12,13,14]. Pfn-1 is involved in regulating smooth muscle functions including actin polymerization and contraction [19, 20]. Other molecules may regulate the activation of Pfn-1 in smooth muscle
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