{beta}-Catenin regulates airway smooth muscle contraction.
beta-Catenin is an 88-kDa member of the armadillo family of proteins that is associated with the cadherin-catenin complex in the plasma membrane. This complex interacts dynamically with the actin cytoskeleton to stabilize adherens junctions, which play a central role in force transmission by smooth muscle cells. Therefore, in the present study, we hypothesized a role for beta-catenin in the regulation of smooth muscle force production. beta-Catenin colocalized with smooth muscle alpha-actin (sm-alpha-actin) and N-cadherin in plasma membrane fractions and coimmunoprecipitated with sm-alpha-actin and N-cadherin in lysates of bovine tracheal smooth muscle (BTSM) strips. Moreover, immunocytochemistry of cultured BTSM cells revealed clear and specific colocalization of sm-alpha-actin and beta-catenin at the sites of cell-cell contact. Treatment of BTSM strips with the pharmacological beta-catenin/T cell factor-4 (TCF4) inhibitor PKF115-584 (100 nM) reduced beta-catenin expression in BTSM whole tissue lysates and in plasma membrane fractions and reduced maximal KCl- and methacholine-induced force production. These changes in force production were not accompanied by changes in the expression of sm-alpha-actin or sm-myosin heavy chain (MHC). Likewise, small interfering RNA (siRNA) knockdown of beta-catenin in BTSM strips reduced beta-catenin expression and attenuated maximal KCl- and methacholine-induced contractions without affecting sm-alpha-actin or sm-MHC expression. Conversely, pharmacological (SB-216763, LiCl) or insulin-induced inhibition of glycogen synthase kinase-3 (GSK-3) enhanced the expression of beta-catenin and augmented maximal KCl- and methacholine-induced contractions. We conclude that beta-catenin is a plasma membrane-associated protein in airway smooth muscle that regulates active tension development, presumably by stabilizing cell-cell contacts and thereby supporting force transmission between neighboring cells.
Jansen
Sepp R
SR
Dept. of Molecular Pharmacology, Univ. of Groningen, The Netherlands.
Van Ziel
Anna M
AM
Baarsma
Hoeke A
HA
Gosens
Reinoud
R
D000199:Actins / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D007211:Indoles / Q000494:pharmacology*; D018021:Lithium Chloride / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000502:physiology; D018995:Myosin Heavy Chains / Q000378:metabolism; D009924:Organ Culture Techniques; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology; D014132:Trachea / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology*
D000199:Actins; D015820:Cadherins; D007211:Indoles; D008301:Maleimides; C538949:PKF115-584; C417521:SB 216763; D051176:beta Catenin; D010569:Perylene; D038362:Glycogen Synthase Kinase 3; D018995:Myosin Heavy Chains; D018021:Lithium Chloride