title: β2-syntrophin and Par-3 promote an apicobasal Rac activity gradient at cell-cell junctions by differentially regulating Tiam1 activity.
abstract: Although Rac and its activator Tiam1 are known to stimulate cell-cell adhesion, the mechanisms regulating their activity in cell-cell junction formation are poorly understood. Here, we identify β2-syntrophin as a Tiam1 interactor required for optimal cell-cell adhesion. We show that during tight-junction (TJ) assembly β2-syntrophin promotes Tiam1-Rac activity, in contrast to the function of the apical determinant Par-3 whose inhibition of Tiam1-Rac activity is necessary for TJ assembly. We further demonstrate that β2-syntrophin localizes more basally than Par-3 at cell-cell junctions, thus generating an apicobasal Rac activity gradient at developing cell-cell junctions. Targeting active Rac to TJs shows that this gradient is required for optimal TJ assembly and apical lumen formation. Consistently, β2-syntrophin depletion perturbs Tiam1 and Rac localization at cell-cell junctions and causes defects in apical lumen formation. We conclude that β2-syntrophin and Par-3 fine-tune Rac activity along cell-cell junctions controlling TJ assembly and the establishment of apicobasal polarity.
authors.affiliation: Cell Signalling Group, Cancer Research UK Paterson Institute for Cancer Research, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Mack
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Porter
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Whalley
authors.forename: Juliane P
authors.initials: JP
authors.lastname: Schwarz
authors.forename: Richard C
authors.initials: RC
authors.lastname: Jones
authors.forename: Azharuddin Sajid Syed
authors.initials: AS
authors.lastname: Khaja
authors.forename: Anders
authors.initials: A
authors.lastname: Bjartell
authors.forename: Kurt I
authors.initials: KI
authors.lastname: Anderson
authors.forename: Angeliki
authors.initials: A
authors.lastname: Malliri
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D016764:Cell Polarity / Q000187:drug effects; D004285:Dogs; D004318:Doxycycline / Q000494:pharmacology; D049029:Dystrophin-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D049029:Dystrophin-Associated Proteins; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; C091824:syntrophin; D020744:rac GTP-Binding Proteins; D004318:Doxycycline