4.5 Article

The polarity protein Scribble positions DLC3 at adherens junctions to regulate Rho signaling

Journal

JOURNAL OF CELL SCIENCE
Volume 129, Issue 19, Pages 3583-3596

Publisher

COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.190074

Keywords

Apical-basolateral polarity; Adherens junctions; Rho GTPase-activating protein; PDZ domain interaction; Tumor suppressor

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Funding

  1. Deutsche Forschungsgemeinschaft (DFG) through the Heisenberg program [OL239/8-2]
  2. DFG [OL239/9-2]

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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.

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