Unregulated ARF6 Activation in Epithelial Cysts Generates Hyperactive Signaling Endosomes and Disrupts Morphogenesis

• DOI: 10.1091/mbc.e09-09-0824
• Publication Date: 2010-05-12T22:44:29Z
• Authors: Jogender S. Tushir; James Clancy; Andrew Warren; Carolyn Wrobel; Joan S. Brugge; Crislyn D'Souza-S...
• Keywords: Internalization; ADP ribosylation factor; Invadopodia

Tumor development in glandular tissues is associated with structural alterations the hollow ducts and spherical structures that comprise such tissues. We describe a signaling axis involving sustained activation of GTP-binding protein, ARF6, provokes dramatic changes organization epithelial cysts, reminiscent tumorigenic phenotypes. In reconstituted basement membrane cultures renal enhanced ARF6 induces formation cell-filled multiple lumens disassembled cadherin-based cell-cell contacts. All these are accompanied by growth factor receptor internalization into endosomes reversed blocking or endocytosis. Receptor localization results hyperactive extracellular signal-regulated kinase leading to Bcl-2 stabilization aberrant cysts. Similarly, hyperproliferative disorganized mammary acini induced chronic stimulation colony-stimulating 1 coupled endogenous constitutive inhibition. These findings identify previously unrecognized link between ARF6-regulated events drive cyst morphogenesis providing new mechanistic insight molecular processes can promote disruption.