title: ARF6-regulated endocytosis of growth factor receptors links cadherin-based adhesion to canonical Wnt signaling in epithelia.
abstract: Wnt signaling has an essential role in embryonic development as well as stem/progenitor cell renewal, and its aberrant activation is implicated in many diseases, including several cancers. β-Catenin is a critical component of Wnt-mediated transcriptional activation. Here we show that ARF6 activation during canonical Wnt signaling promotes the intracellular accumulation of β-catenin via a mechanism that involves the endocytosis of growth factor receptors and robust activation of extracellular signal-regulated kinase (ERK). ERK promotes casein kinase 2-mediated phosphorylation of α-catenin, leading to destabilization of the adherens junctions and a subsequent increase in cytoplasmic pools of active β-catenin and E-cadherin. ERK also phosphorylates LRP6 to amplify the Wnt transduction pathway. The aforementioned Wnt-ERK signaling pathway initiates lumen filling of epithelial cysts by promoting cell proliferation in three-dimensional cell cultures. This study elucidates a mechanism responsible for the switch in β-catenin functions in cell adhesion at the adherens junctions and Wnt-induced nuclear signaling.
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Pellon-Cardenas
authors.forename: James
authors.initials: J
authors.lastname: Clancy
authors.forename: Henriette
authors.initials: H
authors.lastname: Uwimpuhwe
authors.forename: Crislyn
authors.initials: C
authors.lastname: D'Souza-Schorey
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D047390:Casein Kinase II / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D004285:Dogs; D004705:Endocytosis; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000089982:ADP-Ribosylation Factor 6; D015820:Cadherins; D017978:Receptors, Growth Factor; D051153:Wnt Proteins; D051176:beta Catenin; D047390:Casein Kinase II; D048049:Extracellular Signal-Regulated MAP Kinases; D020727:ADP-Ribosylation Factors