Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 5 September 2003:
Vol. 301. no. 5638, pp. 1391 - 1394
DOI: 10.1126/science.1082808
Prev | Table of Contents | Next

Reports

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}

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.



* 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}receptor-biol.duke.edu (R.J.L.); rnusse{at}cmgm.stanford.edu (R.N.)

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
G Protein-coupled Receptor Kinases Phosphorylate LRP6 in the Wnt Pathway.
M. Chen, M. Philipp, J. Wang, R. T. Premont, T. R. Garrison, M. G. Caron, R. J. Lefkowitz, and W. Chen (2009)
J. Biol. Chem. 284, 35040-35048
   Abstract »    Full Text »    PDF »
WNT5A Is a Regulator of Fibroblast Proliferation and Resistance to Apoptosis.
L. J. Vuga, A. Ben-Yehudah, E. Kovkarova-Naumovski, T. Oriss, K. F. Gibson, C. Feghali-Bostwick, and N. Kaminski (2009)
Am. J. Respir. Cell Mol. Biol. 41, 583-589
   Abstract »    Full Text »    PDF »
C5a-Stimulated Recruitment of {beta}-Arrestin2 to the Nonsignaling 7-Transmembrane Decoy Receptor C5L2.
L. H.C. Van Lith, J. Oosterom, A. Van Elsas, and G. J.R. Zaman (2009)
J Biomol Screen 14, 1067-1075
   Abstract »    PDF »
A Coated Vesicle-associated Kinase of 104 kDa (CVAK104) Induces Lysosomal Degradation of Frizzled 5 (Fzd5).
T. Terabayashi, Y. Funato, M. Fukuda, and H. Miki (2009)
J. Biol. Chem. 284, 26716-26724
   Abstract »    Full Text »    PDF »
Inhibition of WNT Signaling by G Protein-Coupled Receptor (GPCR) Kinase 2 (GRK2).
L. Wang, D. Gesty-Palmer, T. A. Fields, and R. F. Spurney (2009)
Mol. Endocrinol. 23, 1455-1465
   Abstract »    Full Text »    PDF »
Xenopus Wntless and the Retromer Complex Cooperate To Regulate XWnt4 Secretion.
H. Kim, S.-M. Cheong, J. Ryu, H.-J. Jung, E.-h. Jho, and J.-K. Han (2009)
Mol. Cell. Biol. 29, 2118-2128
   Abstract »    Full Text »    PDF »
Wnt/{beta}-catenin signaling controls development of the blood-brain barrier.
S. Liebner, M. Corada, T. Bangsow, J. Babbage, A. Taddei, C. J. Czupalla, M. Reis, A. Felici, H. Wolburg, M. Fruttiger, et al. (2008)
J. Cell Biol. 183, 409-417
   Abstract »    Full Text »    PDF »
CaSR stimulates secretion of Wnt5a from colonic myofibroblasts to stimulate CDX2 and sucrase-isomaltase using Ror2 on intestinal epithelia.
I. I. Pacheco and R. J. MacLeod (2008)
Am J Physiol Gastrointest Liver Physiol 295, G748-G759
   Abstract »    Full Text »    PDF »
Ryk cooperates with Frizzled 7 to promote Wnt11-mediated endocytosis and is essential for Xenopus laevis convergent extension movements.
G.-H. Kim, J.-H. Her, and J.-K. Han (2008)
J. Cell Biol. 182, 1073-1082
   Abstract »    Full Text »    PDF »
Wnt3a-Mediated Formation of Phosphatidylinositol 4,5-Bisphosphate Regulates LRP6 Phosphorylation.
W. Pan, S.-C. Choi, H. Wang, Y. Qin, L. Volpicelli-Daley, L. Swan, L. Lucast, C. Khoo, X. Zhang, L. Li, et al. (2008)
Science 321, 1350-1353
   Abstract »    Full Text »    PDF »
Wnt5a Control of Cell Polarity and Directional Movement by Polarized Redistribution of Adhesion Receptors.
E. S. Witze, E. S. Litman, G. M. Argast, R. T. Moon, and N. G. Ahn (2008)
Science 320, 365-369
   Abstract »    Full Text »    PDF »
Differential Wnt Pathway Gene Expression and E-Cadherin Truncation in Sporadic Colorectal Cancers with and without Microsatellite Instability.
P. Ortega, A. Moran, C. de Juan, C. Frias, S. Hernandez, J.-A. Lopez-Asenjo, A. Sanchez-Pernaute, A. Torres, P. Iniesta, and M. Benito (2008)
Clin. Cancer Res. 14, 995-1001
   Abstract »    Full Text »    PDF »
Analysis of Endogenous LRP6 Function Reveals a Novel Feedback Mechanism by Which Wnt Negatively Regulates Its Receptor.
Z. Khan, S. Vijayakumar, T. V. de la Torre, S. Rotolo, and A. Bafico (2007)
Mol. Cell. Biol. 27, 7291-7301
   Abstract »    Full Text »    PDF »
Molecular Scaffolds Regulate Bidirectional Crosstalk Between Wnt and Classical Seven-Transmembrane Domain Receptor Signaling Pathways.
T. Force, K. Woulfe, W. J. Koch, and R. Kerkela (2007)
Sci. STKE 2007, pe41
   Abstract »    Full Text »    PDF »
Wnt5a secretion stimulated by the extracellular calcium-sensing receptor inhibits defective Wnt signaling in colon cancer cells.
R. J. MacLeod, M. Hayes, and I. Pacheco (2007)
Am J Physiol Gastrointest Liver Physiol 293, G403-G411
   Abstract »    Full Text »    PDF »
Functional Desensitization of the Extracellular Calcium-Sensing Receptor Is Regulated via Distinct Mechanisms: Role of G Protein-Coupled Receptor Kinases, Protein Kinase C and {beta}-Arrestins.
S. Lorenz, R. Frenzel, R. Paschke, G. E. Breitwieser, and S. U. Miedlich (2007)
Endocrinology 148, 2398-2404
   Abstract »    Full Text »    PDF »
beta-Arrestin is a necessary component of Wnt/beta-catenin signaling in vitro and in vivo.
V. Bryja, D. Gradl, A. Schambony, E. Arenas, and G. Schulte (2007)
PNAS 104, 6690-6695
   Abstract »    Full Text »    PDF »
Regulation of Wnt Signalling by Receptor-mediated Endocytosis.
A. Kikuchi and H. Yamamoto (2007)
J. Biochem. 141, 443-451
   Abstract »    Full Text »    PDF »
Dvl regulates endo- and exocytotic processes through binding to synaptotagmin..
S. Kishida, K. Hamao, M. Inoue, M. Hasegawa, Y. Matsuura, K. Mikoshiba, M. Fukuda, and A. Kikuchi (2007)
Genes Cells 12, 49-61
   Abstract »    Full Text »    PDF »
Wnt5a Signaling Induces Proliferation and Survival of Endothelial Cells In Vitro and Expression of MMP-1 and Tie-2.
T. N. H. Masckauchan, D. Agalliu, M. Vorontchikhina, A. Ahn, N. L. Parmalee, C.-M. Li, A. Khoo, B. Tycko, A. M.C. Brown, and J. Kitajewski (2006)
Mol. Biol. Cell 17, 5163-5172
   Abstract »    Full Text »    PDF »
beta-Arrestin2 mediates nephrin endocytosis and impairs slit diaphragm integrity.
I. Quack, L. C. Rump, P. Gerke, I. Walther, T. Vinke, O. Vonend, T. Grunwald, and L. Sellin (2006)
PNAS 103, 14110-14115
   Abstract »    Full Text »    PDF »
Wnt Signaling: Multiple Pathways, Multiple Receptors, and Multiple Transcription Factors.
M. D. Gordon and R. Nusse (2006)
J. Biol. Chem. 281, 22429-22433
   Full Text »    PDF »
The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation.
A. Blumenthal, S. Ehlers, J. Lauber, J. Buer, C. Lange, T. Goldmann, H. Heine, E. Brandt, and N. Reiling (2006)
Blood 108, 965-973
   Abstract »    Full Text »    PDF »
Subcellular translocation of the eGFP-tagged TRPL channel in Drosophila photoreceptors requires activation of the phototransduction cascade.
N. E. Meyer, T. Joel-Almagor, S. Frechter, B. Minke, and A. Huber (2006)
J. Cell Sci. 119, 2592-2603
   Abstract »    Full Text »    PDF »
Phosphorylation of Frizzled-3.
W. A. Yanfeng, C. Tan, R. J. Fagan, and P. S. Klein (2006)
J. Biol. Chem. 281, 11603-11609
   Abstract »    Full Text »    PDF »
Dapper 1 Antagonizes Wnt Signaling by Promoting Dishevelled Degradation.
L. Zhang, X. Gao, J. Wen, Y. Ning, and Y.-G. Chen (2006)
J. Biol. Chem. 281, 8607-8612
   Abstract »    Full Text »    PDF »
Wnt signaling: complexity at the surface.
K. M. Cadigan and Y. I. Liu (2006)
J. Cell Sci. 119, 395-402
   Abstract »    Full Text »    PDF »
Arrow (LRP6) and Frizzled2 cooperate to degrade Wingless in Drosophila imaginal discs.
E. Piddini, F. Marshall, L. Dubois, E. Hirst, and J.-P. Vincent (2005)
Development 132, 5479-5489
   Abstract »    Full Text »    PDF »
Genetic Evidence That Drosophila frizzled Controls Planar Cell Polarity and Armadillo Signaling by a Common Mechanism.
M. Povelones, R. Howes, M. Fish, and R. Nusse (2005)
Genetics 171, 1643-1654
   Abstract »    Full Text »    PDF »
Dishevelled (Dvl-2) activates canonical Wnt signalling in the absence of cytoplasmic puncta.
M. J. Smalley, N. Signoret, D. Robertson, A. Tilley, A. Hann, K. Ewan, Y. Ding, H. Paterson, and T. C. Dale (2005)
J. Cell Sci. 118, 5279-5289
   Abstract »    Full Text »    PDF »
The Wnt signalling effector Dishevelled forms dynamic protein assemblies rather than stable associations with cytoplasmic vesicles.
T. Schwarz-Romond, C. Merrifield, B. J. Nichols, and M. Bienz (2005)
J. Cell Sci. 118, 5269-5277
   Abstract »    Full Text »    PDF »
The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity.
J. B. Wallingford and R. Habas (2005)
Development 132, 4421-4436
   Abstract »    Full Text »    PDF »
Dynamic Interaction between the Dual Specificity Phosphatase MKP7 and the JNK3 Scaffold Protein {beta}-Arrestin 2.
E. A. Willoughby and M. K. Collins (2005)
J. Biol. Chem. 280, 25651-25658
   Abstract »    Full Text »    PDF »
The Mechanism of Endogenous Receptor Activation Functionally Distinguishes Prototype Canonical and Noncanonical Wnts.
G. Liu, A. Bafico, and S. A. Aaronson (2005)
Mol. Cell. Biol. 25, 3475-3482
   Abstract »    Full Text »    PDF »
Transduction of Receptor Signals by {beta}-Arrestins.
R. J. Lefkowitz and S. K. Shenoy (2005)
Science 308, 512-517
   Abstract »    Full Text »    PDF »
Wnt signaling in the intestinal epithelium: from endoderm to cancer.
A. Gregorieff and H. Clevers (2005)
Genes & Dev. 19, 877-890
   Abstract »    Full Text »    PDF »
Incredible journey: how do developmental signals travel through tissue?.
A. J. Zhu and M. P. Scott (2004)
Genes & Dev. 18, 2985-2997
   Abstract »    Full Text »    PDF »
The Receptor Tyrosine Kinase Ror2 Associates with and Is Activated by Casein Kinase I{epsilon}.
S. Kani, I. Oishi, H. Yamamoto, A. Yoda, H. Suzuki, A. Nomachi, K. Iozumi, M. Nishita, A. Kikuchi, T. Takumi, et al. (2004)
J. Biol. Chem. 279, 50102-50109
   Abstract »    Full Text »    PDF »
Wnt signals across the plasma membrane to activate the {beta}-catenin pathway by forming oligomers containing its receptors, Frizzled and LRP.
F. Cong, L. Schweizer, and H. Varmus (2004)
Development 131, 5103-5115
   Abstract »    Full Text »    PDF »
LDL receptor-related proteins 5 and 6 in Wnt/{beta}-catenin signaling: Arrows point the way.
X. He, M. Semenov, K. Tamai, and X. Zeng (2004)
Development 131, 1663-1677
   Abstract »    Full Text »    PDF »
Reciprocal Regulation of Angiotensin Receptor-activated Extracellular Signal-regulated Kinases by {beta}-Arrestins 1 and 2.
S. Ahn, H. Wei, T. R. Garrison, and R. J. Lefkowitz (2004)
J. Biol. Chem. 279, 7807-7811
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)