Pathways that negatively regulate airway smooth muscle contraction. (A) The integrin α9β1 negatively regulates airway smooth muscle contraction by colocalizing the polyamine-catabolizing enzyme, spermine spermidine acetyltransferase (SSAT), which directly binds to the α9 subunit with the lipid kinase, PIP5K1γ, the major source of PIP2 in airway smooth muscle, which binds to talin, a direct interactor with the β1 subunit. PIP5K1γ depends on spermine and spermidine for maximal activity, so the local breakdown of spermine and spermidine reduces PIP5K1γ activity, thereby decreasing PIP2 concentrations and the amount of IP3 that is generated by activation of contractile G protein–coupled receptors (such as those activated by acetylcholine or serotonin [5-HT]). (B) The secreted scaffold protein, milk fat globule-EGF factor 8 (MFGE8), inhibits the smooth muscle hypercontractility induced by IL-13, IL-17, and tumor necrosis factor α (TNF) by inhibiting the induction and activation of the small GTPase, RhoA. Active RhoA contributes to smooth muscle contraction by directly activating Rho-associated coiled-coil protein kinase (ROCK) which, in turn, phosphorylates and thereby inactivates myosin light chain phosphatase (MLCP), which normally dephosphorylates myosin.