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Science 301 (5638): 1391-1394

Copyright © 2003 by the American Association for the Advancement of Science

Dishevelled 2 Recruits ß-Arrestin 2 to Mediate Wnt5A-Stimulated Endocytosis of Frizzled 4

Wei Chen,1 Derk ten Berge,2 Jeff Brown,2 Seungkirl Ahn,1 Liaoyuan A. Hu,1 William E. Miller,1* Marc G. Caron,3 Larry S. Barak,4 Roel Nusse,2{dagger} Robert J. Lefkowitz1{dagger}

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 ß-arrestin 2 (ßarr2), which was recruited to Fz4 by binding to phosphorylated Dvl2. These findings provide a previously unrecognized mechanism for receptor recruitment of ß-arrestin and demonstrate that Dvl plays an important role in the endocytosis of frizzled, as well as in promoting signaling.

1 Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
2 Howard Hughes Medical Institute, Department of Developmental Biology, Beckman Center, Stanford University Medical School, Stanford, CA 94305, USA.
3 Howard Hughes Medical Institute, Departments of Cell Biology and Medicine, Duke University Medical Center, Durham, NC 27710, USA.
4 Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.

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* Present address: Department of Molecular Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.

{dagger} To whom correspondence should be addressed. E-mail: lefko001{at} (R.J.L.); rnusse{at} (R.N.)

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