Critical role of actin-associated proteins in smooth muscle contraction, cell proliferation, airway hyperresponsiveness and airway remodeling

Abstract

Asthma is characterized by airway hyperresponsiveness and airway remodeling, which are largely attributed to increased airway smooth muscle contractility and cell proliferation. It is known that both chemical and mechanical stimulation regulates smooth muscle contraction. Recent studies suggest that contractile activation and mechanical stretch induce actin cytoskeletal remodeling in smooth muscle. However, the mechanisms that control actin cytoskeletal reorganization are not completely elucidated. This review summarizes our current understanding regarding how actin-associated proteins may regulate remodeling of the actin cytoskeleton in airway smooth muscle. In particular, there is accumulating evidence to suggest that Abelson tyrosine kinase (Abl) plays a critical role in regulating airway smooth muscle contraction and cell proliferation in vitro, and airway hyperresponsiveness and remodeling in vivo. These studies indicate that Abl may be a novel target for the development of new therapy to treat asthma.

Fig. 1

Mechanisms of Abl-regulated actin polymerization. Stimulation with agonists such as acetylcholine may activate Abl tyrosine kinase, which regulates the formation of the multiprotein complex including Crk-associated substrate (CAS), the adapter protein Abi1 (Abl interactor 1) and N-WASP (neuronal Wiskott-Aldrich Syndrome Protein), which in turn activates N-WASP, actin polymerization and smooth muscle contraction. Activated Abl also catalyzes phosphorylation of GMF-γ (glia maturation factor-γ) at Tyr-104, which induces the dissociation of GMF-γ from Arp2/3, and promotes actin polymerization. Furthermore, contractile agonists promote the association of cortactin (CTTN) with profilin-1 (Pfn-1), which induces actin polymerization and smooth muscle contraction. The interaction of cortactin with Pfn-1 is regulated by cortactin phosphorylation and Abl tyrosine kinase

Fig. 2

Molecular interactions of scaffolding/signaling proteins at or near intergrin-associated junctions. Cytoplasmic tails of integrins connect with actin filaments via actin linker proteins such as talin, vinculin, paxillin and α-actinin. The extracellular domains of integrins interact with the extracellular matrix, forming the integrin-associated junctions. Signaling and scaffolding proteins are assembled at or near the integrin-associated junctions upon contractile activation, which facilitates actin polymerization and the mechanotransduction between the contractile unit and the extracellular matrix. Abi1, Abl interactor 1; Abl, Abelson tyrosine kinase; CAS, Crk-associated substrates; CTTN, cortactin; FAK, focal adhesion kinase; GMF-γ, glia maturation factor-γ; HDAC8, histone deacetylase 8; HSP, heat shock protein; ILK, integrin-linked kinase; MAPK, mitogen-activated protein kinase; MK2, MAP kinase-activated protein (MAPKAP) kinase 2; N-WASP, neuronal Wiskott-Aldrich Syndrome Protein; PAK, p21-activated kinase; Pfn-1, profilin-1; VASP, vasodilator stimulated phosphoprotein

Fig. 3

Novel mechanism for regulation of adherens junctions in smooth muscle. In addition to myosin activation, contractile agonists induce actin polymerization, which promotes the recruitment of β-catenin to N-cadherin. The increase in the protein-protein interaction may enhance the linkage of actin filaments to the adherens junctions, and promote the intercellular force transmission and smooth muscle contraction. C, C terminus; N, N terminus. Linkers, linker proteins such as α-catenin, vinculin and VASP

Fig. 4

Regulation of MAPK pathway and cytokinesis by Abl. Upon the binding of ligands to growth factor receptors, Abl promotes Raf-1 activation by controlling actin dynamics, which in turn modulates the activation of MEK and ERK. In addition, Abl is recruited to the midzone during cytokinesis, which mediates cortactin phosphorylation. Phosphorylated cortactin promotes F-actin assembly, which facilitates contractile ring formation and cytokinesis