title: The polarity protein Scribble positions DLC3 at adherens junctions to regulate Rho signaling.
abstract: The spatial regulation of cellular Rho signaling by GAP proteins is still poorly understood. By performing mass spectrometry, we here identify the polarity protein Scribble as a scaffold for the RhoGAP protein DLC3 (also known as StarD8) at cell-cell adhesions. This mutually dependent interaction is mediated by the PDZ domains of Scribble and a PDZ ligand (PDZL) motif in DLC3. Both Scribble depletion and PDZL deletion abrogated DLC3 junctional localization. Using a RhoA biosensor and a targeted GAP domain, we demonstrate that DLC3 activity locally regulates RhoA-ROCK signaling at and Scribble localization to adherens junctions, and is required for their functional integrity. In a 3D model of cyst development, we furthermore show that DLC3 depletion impairs polarized morphogenesis, phenocopying the effects observed upon Scribble knockdown. We thus propose a new function for Scribble in Rho regulation that entails positioning of DLC3 GAP activity at cell junctions in polarized epithelial cells.
authors: Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, Stuttgart 70569, Germany.
authors: Janina
authors: J
authors: Hendrick
authors: Proteome Center Tübingen, University of Tübingen, Auf der Morgenstelle 15, Tübingen 72076, Germany.
authors: Mirita
authors: M
authors: Franz-Wachtel
authors: Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, Stuttgart 70569, Germany.
authors: Yvonne
authors: Y
authors: Moeller
authors: Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, Stuttgart 70569, Germany.
authors: Simone
authors: S
authors: Schmid
authors: Proteome Center Tübingen, University of Tübingen, Auf der Morgenstelle 15, Tübingen 72076, Germany.
authors: Boris
authors: B
authors: Macek
authors: Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, Stuttgart 70569, Germany monilola.olayioye@izi.uni-stuttgart.de.
authors: Monilola A
authors: 0000-0003-1093-263X
authors: MA
authors: Olayioye
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D018938:Caco-2 Cells; D002448:Cell Adhesion; D016764:Cell Polarity; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D054731:PDZ Domains; D011485:Protein Binding; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D008024:Ligands; D008565:Membrane Proteins; C480591:SCRIB protein, human; C000606740:STARD8 protein, human; D025521:Tumor Suppressor Proteins; C085379:rho GTPase-activating protein; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: Adherens junctions; Apical-basolateral polarity; PDZ domain interaction; Rho GTPase-activating protein; Tumor suppressor