Migration of airway smooth muscle cells

Abstract

Migration of smooth muscle cells is a process fundamental to development of hollow organs, including blood vessels and the airways. Migration is also thought to be part of the response to tissue injury. It has also been suggested to contribute to airways remodeling triggered by chronic inflammation. In both nonmuscle and smooth muscle cells numerous external signaling molecules and internal signal transduction pathways contribute to cell migration. The review includes evidence for the functional significance of airway smooth muscle migration, a summary of promigratory and antimigratory agents, and summaries of important signaling pathways mediating migration. Important signaling pathways and effector proteins described include small G proteins, phosphatidylinositol 3-kinases (PI3-K), Rho activated protein kinase (ROCK), p21-activated protein kinases (PAK), Src family tyrosine kinases, and mitogen-activated protein kinases (MAPK). These signaling modules control multiple critical effector proteins including actin nucleating, capping and severing proteins, myosin motors, and proteins that remodel microtubules. Actin filament remodeling, focal contact remodeling and propulsive force of molecular motors are all coordinated to move cells along gradients of chemical cues, matrix adhesiveness, or matrix stiffness. Airway smooth muscle cell migration can be modulated in vitro by drugs commonly used in pulmonary medicine including beta-adrenergic agonists and corticosteroids. Future studies of airway smooth muscle cell migration may uncover novel targets for drugs aimed at modifying airway remodeling.

Figure 1.

Schematic model illustrating the prominent features of a migrating cell. The leading edge of the cell is represented by the cross-hatched region on the right. Inset A: The leading edge is a site of rapid actin polymerization, depolymerization, and filament branching. Actin nucleating proteins (mDia1, mDia2, VASP) promote filament formation at the plus (barbed) end. G-actin monomers are added by the action of profilin. Actin filaments are severed by gelsolin and depolymerized by cofilin. Actin branching is regulated by small G proteins acting on WAVE, WASP, and proteins of the ARP2/3 complex. The stiffness of the actin gel and traction forces on the matrix are controlled in part myosin II motor proteins that are regulated by activation of multiple kinases (MLCK, PAK, ROCK) and myosin light chain phosphatase (MLCP). Inset B: Within the leading edge are nascent focal contacts (red bars) that form to transiently attach the cell to the matrix. Focal contact components include integrins, adaptor proteins (talin, vinculin, tensin, paxillin), regulatory proteins (Src, CAS, FAK), and proteins controlling myosin II activation (MLCK, PAK, MLCP and ROCK). As the cell migrates, nascent focal contacts mature and move toward the rear of cell. Focal contacts at the rear of the cell (red bars on the left) are disassembled as the cell advances. Disassembly requires the action of multiprotein complexes that depend on microtubules (gray filaments) emanating from the microtubule organizing center (MTOC). Reprinted by permission from Reference .

Figure 2.

Signaling pathways that regulate actin polymerization and myosin II motors in smooth muscle cell migration. Activation of G protein–coupled receptors (GPCR) and receptor tyrosine kinases (RTK) initiates activation of parallel signaling cascades that culminate in actin filament remodeling, and changes matrix adhesiveness and regulation of myosin II motors that generate traction force. Immediate post-receptor events include activation of trimeric G proteins, Src family tyrosine kinases, phospholipase C (PLC) and PIP2, PI3-kinases (PI3-K), and increased Ca²⁺. Multiple small G proteins (RhoA, Rac, Cdc42) and calmodulin (CaM) then activate downstream targets that are shown here in darker shades of red. Some targets are effector proteins that regulate actin polymerization including the formins (mDIA1 and mDIA2), WAVE and WASP, and the ARP2/3 complex. Other targets include members of the MAP kinase family (p38 MAPK and ERK), Rho kinases (ROCK), and p21-activated protein kinases (PAK). The signaling kinases phosphorylate other protein kinases (MAPKAPK, LIMK) or phosphatases (MLCP) to regulate effector proteins (dark blue ovals) that control actin polymerization and traction forces generated by myosin II. Most of the schematic is organized as sets of parallel linear signaling cascades, which is an oversimplification for the sake of clarity. Pathway convergence and crosstalk are known to occur between the pathways shown. Regulation of MLCK is a good example where both positive and negative inputs are integrated to determine the level of myosin II regulatory light chain phosphorylation and traction force. Reprinted by permission from Reference .