title: A Par-1-Par-3-Centrosome Cell Polarity Pathway and Its Tuning for Isotropic Cell Adhesion.
abstract: To form regulated barriers between body compartments, epithelial cells polarize into apical and basolateral domains and assemble adherens junctions (AJs). Despite close links with polarity networks that generate single polarized domains, AJs distribute isotropically around the cell circumference for adhesion with all neighboring cells [1-3]. How AJs avoid the influence of polarity networks to maintain their isotropy has been unclear. In established epithelia, trans cadherin interactions could maintain AJ isotropy [4], but AJs are dynamic during epithelial development and remodeling [5, 6], and thus specific mechanisms may control their isotropy. In Drosophila, aPKC prevents hyper-polarization of junctions as epithelia develop from cellularization to gastrulation [7]. Here, we show that aPKC does so by inhibiting a positive feedback loop between Bazooka (Baz)/Par-3, a junctional organizer [5, 8-10], and centrosomes. Without aPKC, Baz and centrosomes lose their isotropic distributions and recruit each other to single plasma membrane (PM) domains. Surprisingly, our loss- and gain-of-function analyses show that the Baz-centrosome positive feedback loop is driven by Par-1, a kinase known to phosphorylate Baz and inhibit its basolateral localization [8, 11, 12]. We find that Par-1 promotes the positive feedback loop through both centrosome microtubule effects and Baz phosphorylation. Normally, aPKC attenuates the circuit by expelling Par-1 from the apical domain at gastrulation. The combination of local activation and global inhibition is a common polarization strategy [13-16]. Par-1 seems to couple both effects for a potent Baz polarization mechanism that is regulated for the isotropy of Baz and AJs around the cell circumference.
authors.affiliation: Department of Cell & Systems Biology, University of Toronto, 25 Harbord Street, Toronto, ON M5S 3G5, Canada.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Cell & Systems Biology, University of Toronto, 25 Harbord Street, Toronto, ON M5S 3G5, Canada.
authors.forename: R F Andrew
authors.initials: RF
authors.lastname: McKinley
authors.affiliation: Department of Cell & Systems Biology, University of Toronto, 25 Harbord Street, Toronto, ON M5S 3G5, Canada.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: McGill
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON M5S 3M2, Canada; Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Stephane
authors.initials: S
authors.lastname: Angers
authors.affiliation: Department of Cell & Systems Biology, University of Toronto, 25 Harbord Street, Toronto, ON M5S 3G5, Canada. Electronic address: tony.harris@utoronto.ca.
authors.forename: Tony J C
authors.initials: TJ
authors.lastname: Harris
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D016764:Cell Polarity; D018385:Centrosome / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics / Q000502:physiology*; D004848:Epithelium / Q000196:embryology; D054262:Gastrulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; C400774:baz protein, Drosophila; C115015:PKC-3 protein; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3; C472496:Par-1 protein, Drosophila