title: Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4.
abstract: Wnt proteins, regulators of development in many organisms, bind to seven transmembrane-spanning (7TMS) receptors called frizzleds, thereby recruiting the cytoplasmic molecule dishevelled (Dvl) to the plasma membrane.Frizzled-mediated endocytosis of Wg (a Drosophila Wnt protein) and lysosomal degradation may regulate the formation of morphogen gradients. Endocytosis of Frizzled 4 (Fz4) in human embryonic kidney 293 cells was dependent on added Wnt5A protein and was accomplished by the multifunctional adaptor protein beta-arrestin 2 (betaarr2), which was recruited to Fz4 by binding to phosphorylated Dvl2. These findings provide a previously unrecognized mechanism for receptor recruitment of beta-arrestin and demonstrate that Dvl plays an important role in the endocytosis of frizzled, as well as in promoting signaling.
authors.affiliation: Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Derk
authors.initials: D
authors.lastname: ten Berge
authors.forename: Jeff
authors.initials: J
authors.lastname: Brown
authors.forename: Seungkirl
authors.initials: S
authors.lastname: Ahn
authors.forename: Liaoyuan A
authors.initials: LA
authors.lastname: Hu
authors.forename: William E
authors.initials: WE
authors.lastname: Miller
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.forename: Larry S
authors.initials: LS
authors.lastname: Barak
authors.forename: Roel
authors.initials: R
authors.lastname: Nusse
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lefkowitz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D004705:Endocytosis; D051157:Frizzled Receptors; D006801:Humans; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000494:pharmacology; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D048868:Adaptor Proteins, Signal Transducing; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D002966:Clathrin; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; C000606582:Dvl2 protein, mouse; D051157:Frizzled Receptors; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C000606588:dsh protein, Drosophila; D011493:Protein Kinase C