Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4.
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.
Chen
Wei
W
Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
ten Berge
Derk
D
Brown
Jeff
J
Ahn
Seungkirl
S
Hu
Liaoyuan A
LA
Miller
William E
WE
Caron
Marc G
MG
Barak
Larry S
LS
Nusse
Roel
R
Lefkowitz
Robert J
RJ
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
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