title: Par3 integrates Tiam1 and phosphatidylinositol 3-kinase signaling to change apical membrane identity.
abstract: Pathogens can alter epithelial polarity by recruiting polarity proteins to the apical membrane, but how a change in protein localization is linked to polarity disruption is not clear. In this study, we used chemically induced dimerization to rapidly relocalize proteins from the cytosol to the apical surface. We demonstrate that forced apical localization of Par3, which is normally restricted to tight junctions, is sufficient to alter apical membrane identity through its interactions with phosphatidylinositol 3-kinase (PI3K) and the Rac1 guanine nucleotide exchange factor Tiam1. We further show that PI3K activity is required upstream of Rac1, and that simultaneously targeting PI3K and Tiam1 to the apical membrane has a synergistic effect on membrane remodeling. Thus, Par3 coordinates the action of PI3K and Tiam1 to define membrane identity, revealing a signaling mechanism that can be exploited by human mucosal pathogens.
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Travis R
authors.initials: TR
authors.lastname: Ruch
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158.|Cancer Research UK Beatson Institute, University of Glasgow, Glasgow G61 1BD, United Kingdom.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom.
authors.forename: David M
authors.initials: DM
authors.lastname: Bryant
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158.|Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158.
authors.forename: Keith E
authors.initials: KE
authors.lastname: Mostov
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143 joanne.engel@ucsf.edu.
authors.forename: Joanne N
authors.initials: JN
authors.lastname: Engel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018929:Cell Culture Techniques; D018797:Cell Cycle Proteins / Q000378:metabolism* / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology*; D004285:Dogs; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D019108:Tight Junctions / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; C509689:PARD3 protein, human; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D058539:Phosphatidylinositol 3-Kinase; D020830:rac1 GTP-Binding Protein