title: IQGAP1-dependent scaffold suppresses RhoA and inhibits airway smooth muscle contraction.
abstract: The intracellular scaffold protein IQGAP1 supports protein complexes in conjunction with numerous binding partners involved in multiple cellular processes. Here, we determined that IQGAP1 modulates airway smooth muscle contractility. Compared with WT controls, at baseline as well as after immune sensitization and challenge, Iqgap1-/- mice had higher airway responsiveness. Tracheal rings from Iqgap1-/- mice generated greater agonist-induced contractile force, even after removal of the epithelium. RhoA, a regulator of airway smooth muscle contractility, was activated in airway smooth muscle lysates from Iqgap1-/- mice. Likewise, knockdown of IQGAP1 in primary human airway smooth muscle cells increased RhoA activity. Immunoprecipitation studies indicated that IQGAP1 binds to both RhoA and p190A-RhoGAP, a GTPase-activating protein that normally inhibits RhoA activation. Proximity ligation assays in primary airway human smooth muscle cells and mouse tracheal sections revealed colocalization of p190A-RhoGAP and RhoA; however, these proteins did not colocalize in IQGAP1 knockdown cells or in Iqgap1-/- trachea. Compared with healthy controls, human subjects with asthma had decreased IQGAP1 expression in airway biopsies. Together, these data demonstrate that IQGAP1 acts as a scaffold that colocalizes p190A-RhoGAP and RhoA, inactivating RhoA and suppressing airway smooth muscle contraction. Furthermore, our results suggest that IQGAP1 has the potential to modulate airway contraction severity in acute asthma.
authors.forename: Mallar
authors.initials: M
authors.lastname: Bhattacharya
authors.forename: Aparna
authors.initials: A
authors.lastname: Sundaram
authors.forename: Makoto
authors.initials: M
authors.lastname: Kudo
authors.forename: Jessica
authors.initials: J
authors.lastname: Farmer
authors.forename: Previn
authors.initials: P
authors.lastname: Ganesan
authors.forename: Amin
authors.initials: A
authors.lastname: Khalifeh-Soltani
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Arjomandi
authors.forename: Kamran
authors.initials: K
authors.lastname: Atabai
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Huang
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism / Q000503:physiopathology; D018345:Mice, Knockout; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000276:immunology / Q000503:physiopathology*; D021381:Protein Transport; D015398:Signal Transduction; D014132:Trachea / Q000276:immunology / Q000503:physiopathology; D020703:ras GTPase-Activating Proteins / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
chemical_list: C101203:IQ motif containing GTPase activating protein 1; D020703:ras GTPase-Activating Proteins; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein