Fig. 1

a: The process of ASMC migration can be divided into 5 steps: cell polarization, protrustion, adhesion, contraction, and retraction. These steps are controlled by specific signaling proteins, which are modulated by external stimuli. The signaling proteins are described in Fig. 1A. b: Cell migration is initiated by activation of receptors such as G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTK), and integrins, which trigger downstream intracellular signaling, resulting in airway smooth muscle cell (ASMC) migration. An important contributing factor to ASMC migration is actin polymerization, which is a proximal event that propels the leading cell edge towards external stimuli. Various mediators and the extracellular matrix (ECM), for example PDGF, HB-EGF, TGF-β, can activate these membrane receptors. Post-receptor activation, there is downstream induction of trimeric G proteins, Src tyrsoine kinases, phospholipase C, PIP2, c-Abl, and PI3K. This is followed by subsequent activation of signaling proteins (Cdc42, Ras, Rac, Rho, Cortactin, FAK, Akt, PKA, etc), which regulate cell polarization, actin polymerization and traction force. There are various downstream targets that are integral to these processes including the effector proteins mDIA1, WAVE, WASP, ARP2/3 complex. Additional downstream regulators include members of the MAPK family p38 MAPK, ERK, Rho kinase (ROCK), and p21-activated protein kinases (PAK). This results in further phosphorylation of other protein kinases including MAPKAPK, LIMK or phosphatases like MLCP, which then regulate effector proteins that control actin polymerization (HSP20, HSP27, Cortactin, Pin-1, Cofilin) and traction forces (myosin II). Actin polymerization is controlled via complex processes that involve actin branching, actin elongation, and de-branching. This figure is a simplified illustration of the various signaling pathways, which is in reality far more complex then this. These processes are thoroughly reviewed by Tang [127] and Gerthoffer et al. [128]. Red arrows indicate inhibition, green arrows indicate stimulation. Purple circles indicate the most upstream signaling proteins, lightest blue circles indicate effector proteins, including small G proteins, and darker blue circles represent proteins that directly regulate ASMC migration